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MVP and vaults: a role in the radiation response

MVP and vaults: a role in the radiation response Vaults are evolutionary highly conserved ribonucleoproteins particles with a hollow barrel-like structure. The main component of vaults represents the 110 kDa major vault protein (MVP), whereas two minor vaults proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (vPARP) and the 240 kDa telomerase-associated protein-1 (TEP-1). Additionally, at least one small and untranslated RNA is found as a constitutive component. MVP seems to play an important role in the development of multidrug resistance. This particle has also been implicated in the regulation of several cellular processes including transport mechanisms, signal transmission and immune responses. Vaults are considered a prognostic marker for different cancer types. The level of MVP expression predicts the clinical outcome after chemotherapy in different tumour types. Recently, new roles have been assigned to MVP and vaults including the association with the insulin-like growth factor-1, hypoxia-inducible factor-1alpha, and the two major DNA double-strand break repair machineries: non-homologous endjoining and homologous recombination. Furthermore, MVP has been proposed as a useful prognostic factor associated with radiotherapy resistance. Here, we review these novel actions of vaults and discuss a putative role of MVP and vaults in the response to radiotherapy. Keywords: major vault protein, radiotherapy, prognosis, radiation response Review acidic pH, and half vaults can be exchanged to form Major vault protein: an overview of structure and new vaults. Based on these features and on its large composition interior volume, which may encapsulate hundreds of Vaults are ribonucleoprotein particles with a hollow bar- proteins, recent interest in recombinant vaults derives rel-like structure [1] and a mass of 13 MD. In mammals, from nanoparticle research trying to exploit vaults as it is composed of three proteins: MVP (104 kD), the drug delivery system [7,8]. vault poly(adenosine diphosphate-ribose) polymerase Thesequences ofthe2 otherproteins, which are not also known as VPARP (193 kD), and telomerase-asso- part of this shell-like structure and probably reside at ciated protein-1 TEP1 (240 kD), and small untranslated the top center of the caps or within the vaults, are iden- RNA (vRNA) of 141 bases. MVP constitutes more than tified and are present also in the human genome. 70% of the total mass of the complex [2-4], while vARN VPARP presumably ribosylates substrates and TEP1 is represents less than 5% [5]. The molecular architecture important for stabilization of vRNA. Molecular compo- of the rat liver vault complex was recently elucidated at sition of the vault has been roughly estimated as 78-96 high resolution [6]. A vault consists of 2 dimers of half- MVPs, eight VPARPs, two TEP1s, and at least six copies vaults, which align at their waists to form together a of vRNA [9]. Both the high degree of evolutionary con- barrel-like structure with the overall dimensions of 72 × servation and the complex structure of vault particles, as well as its broad distribution in tissues, suggest an 41 × 41 nm. Each half-vault comprises 39 identical major vault proteins (MVP), the major self-assembling important function in cellular processes [10]. Although structural component (Figure 1). Interestingly, vaults vaults have been proposed to play a role in drug resis- can open, the two halves can dissociate at their waists at tance, nucleocytoplasmic transport, and regulation of signaling, a definitive function for MVP or vaults has yet -/- to be assigned as MVP knockout mice (MVP )donot * Correspondence: lhenriquez@dcc.ulpgc.es Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr have phenotypes consistent with these in vitro observa- Negrín. C/Barranco de La Ballena s/n, 35010, Las Palmas de Gran Canaria, tions[11].Thissuggeststhateventhoughthe major Spain -/- component of the vault particle is absent in MVP - Full list of author information is available at the end of the article © 2011 Lara et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lara et al. Radiation Oncology 2011, 6:148 Page 2 of 9 http://www.ro-journal.com/content/6/1/148 to xenobiotics such as bronchial cells and cells lining the intestine [19]. Most of the vaults are located in the cytoplasm, although a small fraction of these particles apparently is also localized at or near the nuclear mem- brane and the nuclear pore complex [20,21]. The wide- spread of vaults in many diverse organisms and cell types suggests that their function is essential to eukaryo- tic cells. Interaction Partners and Putative Functions of Vaults The detailed insight on the structure of MVP and vaults contrasts with the poor understanding of their endogen- ous function. Several observations though indicate that MVP is directly involved in major cytoplasmic signal transduction cascades. In EGF-stimulated cells, tyrosine- Figure 1 Overall structure of the vault shell.Onemoleculeof phosphorylated MVP complexes with the SH2-domain- MVP is colored in tan, and the others are colored in purple. (Left) containing tyrosine phosphatase SHP-2 and interacts Side view of the ribbon representation. The whole vault shell comprises a 78-oligomer polymer of MVP molecules. The size of the with ras-activated downstream kinase Erk, presumably whole particle is ~670 Å from the top to the bottom and ~400 Å in to fine-tune the activity of the Erk-downstream target maximum diameter. The particle has two protruding caps, two Elk-1 [22]. But tyrosine-phosphorylated MVP also binds shoulders, and a body with an invaginated waist. Two half-vaults are to the SH2-domain of Src-kinase and downregulates associated at the waist with N-terminal domains of MVP. (Right) Top view of the ribbon representation. The maximum diameter of the EGF-dependent ERK activation in Src overexpressing cap is ~200 Å. The outer and the inner diameters of the cap-ring cells [23]. Likewise MVP also binds to the tumour sup- are shown. Figure reproduced from Tanaka et al. (2009) with pressor phosphatase and tensin homolog deleted on permission from The American Association for the Advancement of chromosome 10 (PTEN) and a significant quantity of Science (Sciences Magazine). endogenous PTEN associates with vault particles in HeLa cells, thus suggesting a regulatory role for MVP in mice, and vault particles are no longer detected, the the phosphoinositide 3-kinase/Akt (PI 3-kinase/Akt) sig- remaining components TEP1, VPARP, and vRNA might naling pathway [24]. However, MVP-PTEN-interaction still interact and possibly fulfill a functional role. might only be relevant for nuclear import of PTEN The human gene encoding MVP has been located in thereby regulating the nuclear function of PTEN ([25], chromosome 16 (16p11.2) [12], approximately 27 cM see below). Eventually, the identification of the specific proximal to the gene location of the multidrug resis- growth factor-regulated MVP phosphorylation sites and tance protein-1 (MRP1, also designated as ABCC1) [12]. the complexed interaction partner on MVP in response However, although both the ABCC1 and MVP maps to to growth factor stimulation are required to reveal a the short arm of chromosome 16, they are rarely coam- scaffold or direct regulatory function of MVP/vaults on plified and are normally not located within the same these signal transduction cascades. amplicon and can be switched on separately [12,13]. Likewise, a co-immunoprecipitation approach revealed Analysis of the human MVP gene revealed a TATA- that the UV-induced phosphorylation status of MVP less promoter, which also lacks other core-promoter ele- affects the capacity of the constitutive photomorpho- ments but harbors several putative transcription factor genic 1 ubiquitin ligase (COP1) to interact with the binding sites, including an inverted CCAAT box, a p53- transcription factor c-jun. In unstressed cells, cytoplas- binding site, and a GC box element [14]. In silico analy- mic MVP/vault binds to and modifies COP1, presum- sis identified a putative STAT-binding site that strongly ably via the other vault components. Following shuttling resembles an interferon-g-activated site element (GAS), into the nucleus, COP1 complexes with c-jun with high which binds preferentially to STAT1 homodimers [15]. affinity and suppresses its transcriptional activity by tar- Disruption of the STAT-binding site reduces basal MVP geting c-jun for degradation. After UV irradiation, phos- promoter activity, suggesting a role of JAK/STAT signals phorylated MVP does not interact with COP1 anymore, in the activation of MVP expression [16]. With up to eventually leading to the alleviation of COP1-c-jun- 10 particles per cell, vaults are abundantly present in complex formation. Free c-jun subsequently drives AP- many different cell types, although its expression varies 1-controlled gene expression [26]. Negative regulation of among tissues. Vaults are most numerous in macro- downstream signaling has also been identified on the phages [17,18] and epithelial cells with secretory and level of the hypoxia-inducible factor-1a (HIF-1). HIF-1a excretory functions as well as cells chronically exposed and MVP-expression are increased under hypoxia. Lara et al. Radiation Oncology 2011, 6:148 Page 3 of 9 http://www.ro-journal.com/content/6/1/148 However, the stability of HIF-1a protein is enhanced to resistant lung cancer cell line diverting cytostatic drugs higher extents in MVP-knockdown cells. Direct complex from intracellular targets and conferring multidrug resis- formation of vaults with HIF-1a,PHDsand pVHL was tance (MDR) [19]. Several proteins have been linked to demonstrated and suggests that MVP/vault might act as MDR, such as the ABC-drug transporter p-Glycoprotein scaffold protein for ubiquitination and degradation of (P-gp, also designated as ABCB1), members of the mul- HIF1a [27] and thereby affects hypoxia-regulated tidrug resistant protein family (ABCC1, ABCC2, expression of HIF-1a-dependent gene expression. ABCC3), the human breast cancer resistance protein -/- The generation of MVP -mice did not reveal any (BCRP) and the lung-resistance protein (LRP) [36,38,39]. further indications on an essential role of MVP and The LRP was initially discovered due to its high expres- vaults during embryogenesis and in the cellular pro- sion level in a multidrug-resistant but ABCB1-negative cesses in tissues of adult mice under normal environ- lung cancer cell line [19] and has been identified in mental conditions. Furthermore, both embryonic stem 1995 to be the human major vault protein [2]. Thereby, -/- cells and bone marrow cells derived from MVP -mice a first link between the MDR and vaults was established. display a similar sensitivity towards classic cytostatic MVP has been detected in 78% of 61 human cancer agents as their wildtype counterpart cells, and normal cell lines, and its expression levels correlate with resis- tissue toxicity towards doxorubicin in vivo is unchanged tance against a variety of MDR-related and unrelated in the MVP-deficient mice. Interestingly though and drugs [40,41]. Furthermore, upregulation of the MVP unexpectedly identified, MVP and vaults are part of the expression level was determined in multiple human can- effective innate immune response and contribute to the cer cell lines also on treatment with anticancer agents, uptake and clearance of lung pathogens such as Pseudo- including anthracyclins, etoposide and cisplatin, further monas aeruginosa via lipid rafts in lung epithelial cells, supporting a putative link between treatment sensitivity and eventually resistance to lethality [28]. Furthermore, and cellular stress adaptation to cytotoxic agent the activation of MVP-expression by interferon g [19,42-47], and overexpression of MVP is also frequently through the JAK/STAT pathway and enhanced expres- observed at the early steps of resistance selection sion of MVP in macrophages and in dendritic cells sug- [45,46,48,49]. Multiple preclinical studies have corrobo- gest a clear relationship with the immune system rated this link between MDR and the MVP expression [16,29]. However, despite the high abundance of MVP/ level in cancer cells, despite some contradicting studies vaults in MVP-wildtype dendritic cells, no differences in and the fact that the MVP knockout mouse does not dendritic cell migration and antigen presentation and T- show enhanced hypersensitivity to cytostatics. However, -/- cell responses could be observed in MVP -mice. In this might be due to differential cancer to normal cell line treatment sensitivities or the upregulation of other human beings, a strong up-regulation of vault expres- sion during dentritic cell culturing was observed, pro- ABC-transporters or unknown mechanisms of MDR on posing that vaults act as components in the cascade of disruption of functional MVP [11,50]. events regulating dentritic cell effector function [30]. Vaults may mediate multi-drug resistance by the Besides the activation of MVP by interferon, several transport of drugs away from their subcellular targets, other observations indicate that MVP might be involved by the extrusion from the nucleus and/or the sequestra- in immunological responses [31]. It has been reported a tion of drugs into exocytotic vesicles. Either through dramatic induction of vRNA expression in response to these exocytotic vesicles or pump molecules like infection with Epstein-Barr virus [32,33], and vRNA ABCB1, ABCC1, or breast cancer resistance protein at induction has been has been suggested as playing the plasma membrane, the intracellular potency of these important roles in innate immunity [34]. This led to cytotoxic agents will be reduced [51]. Alternatively, the speculate that vRNA/vaults could be involved in anti- two vault-associated VPARP poly(adenosine dipho- viral defence. sphate-ribose) polymerase or TEP-1 may fulfil a protec- Finally, the hollow structure, the rapid movements, the tive function of the genome and thereby contribute to a distinct subcellular localisation (as for example at the drug-resistance profile. Concomitant operation of sev- nuclear membrane), and the in vitro and clinical corre- eral drug resistance mechanisms may often be necessary lations with drug resistance in several types of human to cause the phenotype of MDR, and co-expression of cancers led to the hypothesis that vaults might represent MVP and ABCC1 frequently occurs and associates with rather promiscuous transport vehicles [35-37]. increased drug resistance levels in MDR-selected tumour cells [40]. Interestingly, up-regulation of MVP Drug resistance: the best known role of MVP could be linked in a series of MDR cell lines with a low The MVP has originally been identified as the lung and intermediate level of drug resistance with subse- quent up-regulation of ABCB1 leading to high levels of resistance protein [2]. LRP was discovered almost 20 drug resistance. These findings point the MVP years ago as a protein overexpressed in a multidrug- Lara et al. Radiation Oncology 2011, 6:148 Page 4 of 9 http://www.ro-journal.com/content/6/1/148 expression level as a marker for low level of drug resis- also result in low expression levels of Bax. On the level tance, which is clinically more relevant [19,45,48]. of NHEJ, an inverse correlation between high MVP and Furthermore, several studies reported that the expres- low expression levels of Ku70/80 and pro-apoptotic bax sion of MVP is a predictive marker in several tumour was identified in a cohort of 160 patients with localized types for the response to chemotherapy [52,53]. cervix carcinoma. Interestingly, low Ku70/80 expression Interestingly, human vRNAs produce several small was also associated with upregulated Bcl-2, altered p53, RNAs (svRNAs) by mechanisms different from those in and increased proliferation in this set of patients [59]. Despite the lack of mechanistic insights these data sug- the canonical microRNA (miRNA) pathway. svRNAb gest that overexpression of MVP and vaults might be downregulates CYP3A4, a key enzyme in drug metabo- lism.Thisfinding contributestounderstandthe role of involved in a carcinogenic process with resultant geno- vaults particles in drug resistance, proposing a novel mic instability due to suppressed NHEJ. Though function to vRNAs that may help explain this associa- enhanced proliferative activity, subsequent tumour pro- tion [54]. gression and enhanced treatment resistance requires at the same time an upregulated apoptotic threshold, A novel role for MVP: implications in radiotherapy which might be activated through the suppression of In recent years, several findings indicate a link between Bax, upregulation of Bcl-2, mutated p53-status and MVP and vaults not only to drug-resistance based on its upregulation of the IGF-1R and downstream signalling putative drug-exporter function, but also to DNA- cascades. Eventually, only molecular dissection of the damage and DNA-damage-repair. MVP transcription key signal transduction cascades leading to reduced and protein levels are increased in response to various NHEJ-activity in MVP-overexpressing and MVP- DNA-damaging agents, including ionizing radiation (IR) depleted cells will elucidate the association between [55]. Interestingly, VPARP and, to lesser extent, TEP-1- MVP/vaults, NHEJ and a deregulated apoptotic thresh- deficient mice, have an increased incidence of carcino- old. Moreover, MVP increases with age both in vitro gen-induced colon tumours [56]. These findings indicate andinvivo,andthatage-related upregulation of MVP that vaults may play a role in facilitating DNA repair facilitates apoptosis resistance of senescent human processes. diploid fibroblasts based on the interaction with c-Jun- The high cytotoxicity of IR is mainly based on its abil- mediated downregulation of BCL-2 [60]. Thus, MVP is itytoinduceDNA double strand breaks (DSB)via gen- suggested to be playing an important role in the resis- eration of reactive oxygen species. DSB can be repaired tance of senescent fibroblasts to apoptosis by modula- tion of BCL-2 expression by JNK pathway, regulating by the two major DSB repair machineries: homologous recombination (HR) and non-homologous end joining cellular signaling and survival and being a potential (NHEJ). The fact that error-free repair by HR depends therapeutic target for modulation of resistance to apop- on thepresenceofan intactsister chromatid restricts tosis implicated in aging modulation and cancer treat- this pathway to occur during S and G2 phases of the ment [61]. cell cycle. This is, in contrast to error-prone repair by A novel link between the intracellular level of MVP NHEJ which can function throughout the cell cycle and and homologous recombination, the second DNA-DSB- is therefore thought to be the predominant DSB repair repair machinery, has recently been identified as part of pathway in mammalian cells. On the other hand, HR the cellular stress response to ionizing radiation (Pre- represents the more interesting target to sensitize speci- sented in ESTRO 29; S 51, 129 oral). MVP-depleted fically tumor cells to DNA damaging agents leading to tumour cells are more radiosensitive than their wildtype an enhanced therapeutic window. cognate cells, probably due to direct interference with MVP and vaults have recently been linked to both homologous recombination. In comparison to control major DSB-machineries. Ku70 and Ku80 are key pro- cells, Rad51-foci are strongly reduced in irradiated but teinsinNHEJ, andalsoplayastrongregulatoryrolein MVP-depleted cells and thus vaults may coordinate cor- apoptosis through Bax/Bcl-2 interactions [57,58]. The rect HR-complex formation at the site of the DSB. DNA end-joining protein Ku70 inhibits apoptosis by Vaults might also guarantee sufficient protein level of sequestering Bax away from the mitochondria. However, Rad51 required for homologous recombination via coor- newly synthesized Bax undergoes ubiquitination, which dinated Rad51 expression. It has been reported that negatively regulates its proapoptotic function by labeling MVP mediates nuclear import of PTEN and regulates it for proteasomal degradation. Interestingly, ubiquiti- its nuclear function [24,62]. Nuclear PTEN expression is high in untransformed cells but decreases with tumour nated Bax associates with Ku70, which mediates Bax progression. While cytoplasmic PTEN inhibits the phos- deubiquitination, simultaneously generating the active phoinositol-3-kinase (PI3K)/AKT pathway, nuclear form of Bax but sequestered away from the mitochon- dria [57]. Low expression level of Ku70 might therefore PTEN inhibits phosphorylation of MAPK and Lara et al. Radiation Oncology 2011, 6:148 Page 5 of 9 http://www.ro-journal.com/content/6/1/148 consequently reduces the expression of cyclin D leading Table 1 Clinical studies investigating the association between MVP and therapy response and survival to a G0/G1 cell cycle arrest. Though, PTEN also acts as cofactor for the transcription factor E2F1, driving Author Patients (n) Tumour Response DFS OS expression of RAD51. Cells deficient in PTEN have Izquierdo [13] 57 Ovarian cancer Yes Yes Yes reduced capacity of homologous recombination-depen- Schadendorf [90] 71 Melanoma Yes dent DNA repair, most probably due to reduced levels Ramani [95] 21 Neuroblastoma No of RAD51. Thereby, PTEN is also important for the Dingemans [96] 36 NSCLC No No maintenance of chromosomal stability reducing the inci- Linn [97] 70 Breast cancer No dence of spontaneous double strand breaks. Interest- Uozaki [98] 60 Osteosarcoma Yes Yes ingly, loss of PTEN in tumour cells and concomitantly Arts [81] 115 Ovarian cancer No No No reduced homologous recombination can thereby be Pohl [99] 99 Breast cancer No No No exploited by the inhibiton of PARP, creating a situation Volm [100] 87 NSCLC Yes No of synthetic lethality [63,64]. Since MVP and vaults are Goff [101] 29 Ovarian cancer No involved in nuclear import of PTEN and homologous Pohl [102] 68 Colorrecto No recombination, it will be of interest to determine Diestra [89] 83 Bladder cancer Yes whether the MVP expression level also affects genomic Harada [103] 57 NSCLC Yes instability and sensitivity to PARP-inhibition. Silva [93] 78 HNSCC Yes Yes Despite the fact that we have so far only limited DFS, disease-free survival; OS, overall survival; NSCLC, non-small cell lung insights into the mechanisms how MVP and vault inter- cancer; HNSCC, head-and-neck squamous cell carcinoma. act with the two double strand-break repair machineries, these results indicate that MVP and vaults may co-regu- type of malignancy is still questionable, and standardized late correct DNA repair of spontaneous and treatment- detection methods are needed. Nevertheless, a direct induced double strand breaks. Due to the barrel-like association between MVP expression and therapy resis- structure vaults may act as carriers not only for toxic tance and prognosis in patients suffering from acute agents but also for the coordinated intracellular trans- myeloid leukaemia was identified [67-70]. A positive port of DNA-repair related proteins and thereby act as correlation between MVP expression and worse patient scaffold protein or shuttling vector. Otherwise, the prognosis, therapy response, and survival rate has been vaults associated proteins VPARP or TEP1 might play a reported in acute lymphoblastic leukaemia patients so far not-identified role for correct DNA repair, which [71-73], and similar results have been described in adult could only be achieved as part of an intact vaults. As T-cell leukaemia [74,75] and multiple myeloma [76-78]. indicated above, in vitro studies revealed that gene On the other hand, relatively few studies have expression levels of MDR-related proteins increased addressed the role of MVP in solid tumours, with con- after fractionated irradiation. It is well known that radia- tradictory findings. Thus, the quality of MVP as prog- tion treatment can induce resistance to various cytotoxic nostic marker in ovarian carcinoma is unclear so far, drugs [65], although the molecular basis of this interac- with positive [79,80] and negative [81,82] associations tion are complex. Irradiated cell lines showed a signifi- reported. Result regarding to breast cancer [83,84], non- cant resistance to cisplatin, doxorubicin and small cell lung cancer [85,86], or different types of sar- bendamustine, suggesting a novel mechanism in the comas are inconclusive [87,88]. On the other hand, appearance of MDR, which might involve a radiation- MVP has been established as a reliable factor for induced increment of LRP/MVP [66]. response to chemotherapy in bladder cancer patients [89], melanoma [90], and determining the aggressive MVP and tumour malignancies: vaults as a predictive/ phenotype of testicular germ-cell tumours [91] and glio- prognostic marker blastoma [92]. Numerous studies were performed to clarify the expres- With regard to a putative role of MVP in radiation sion status of MVP in human malignancies as a predic- resistance, it has been reported that MVP expression is tive and prognostic marker for the chemotherapy strongly associated with local-disease free survival and response and patient prognosis (Table 1). These studies cancer-specific survival in a series of patients suffering mainly focused on haematological malignancies. The from squamous cell carcinoma of the oropharynx who results should be viewed with caution, since they will be received primary radiotherapy with curative intent (in influenced by factors such as 1) MVP detection assays univariate and multivariate analyses) [93]. Elevated MVP (especially referred to gene expression), 2) number of expression seems to be associated with a RT-resistant patients included, or 3) type of statistical analysis per- subset of patients, proposing MVP as a novel useful formed (univariate vs. multivariate analysis). The quality prognostic marker associated with RT [93]. The under- of MVP as a prognostic or predictive marker in this lying mechanisms behind this association are not well Lara et al. Radiation Oncology 2011, 6:148 Page 6 of 9 http://www.ro-journal.com/content/6/1/148 List of abbreviations defined today but might be linked to the above cited HIF-1: hypoxia-inducible factor-1; HR: homologous recombination; MDR: role of MVP in DNA repair and apoptotic threshold. multidrug resistance; MRP: multidrug resistance protein; MVP: major vaults The complexity but also interest in MVP as a predictive protein; NHEJ: non-homologous end joining; RT: radiotherapy; TEP-1: telomerase-associated protein-1; VPARP: vault poly(adenosine diphosphate- and/or prognostic marker is also illustrated in cervical ribose) polymerase. cancer patients receiving combined radiochemotherapy [52]. Increased MVP and IGF-1R expression levels were Acknowledgements We thank Professor Adrian Begg for helpful comments during the related to a small cohort of cervical cancer patients with preparation of this manuscript. reduced long-term local control, in patients who other- wise achieved clinical complete response to radioche- Author details Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr motherapy. High MVP expression was strongly related to Negrín. C/Barranco de La Ballena s/n, 35010, Las Palmas de Gran Canaria, high IGF1-R expression, which is associated with chemo- Spain. Clinical Sciences Department, Universidad de Las Palmas de Gran and radioresistance in localized cervical carcinoma Canaria. C/Dr. Pasteur s/n, 35016, Las Palmas de Gran Canaria, Spain. Instituto Canario de Investigación del Cáncer, Canary Islands, Spain. patients [94]. This association suggests that both proteins Radiation Oncology Department, University Hospital Zürich. Raemistrasse need to be expressed to confer chemoradioresistance in 100CH-8091, Zürich, Switzerland. cervical cancer. This was further supported by a sub- Authors’ contributions group of patients who showed low levels of MVP and PCL has been involved in revising the manuscript critically for important IGF1R and who presented excellent survival rates once intellectual content and has given final approval of the version to be [52]. All of the responding patients with negative or fairly published, MP has been involved in drafting the manuscript and has made substantial contributions to conception and design, MZ has made positive (low MVP) tumours were free of local, distant or substantial contributions to conception and design, LAHH has been involved death related disease. These results were similar to the in drafting the manuscript and has made substantial contributions to ones previously obtained for IGF-1R as a prognostic mar- conception and design. All authors read and approved the final manuscript. ker [94]. Combination analysis was performed grouping Competing interests MVP and IGF-1R expression in tumours, showing that The authors declare that they have no competing interests. all responding patients withlow MVP/IGF-1R tumours Received: 3 August 2011 Accepted: 31 October 2011 were free of local disease, relapse or death related disease. Published: 31 October 2011 As illustrated by these studies, we are still far away to have identified a mechanistic link between MVP expres- References sion level and treatment response, and it is still a matter 1. Kedersha NL, Heuser JE, Chugani DC, Rome LH: Vaults. III. Vault ribonucleoprotein particles open into flower-like structures with of debate in how far vaults are involved in chemo- and octagonal symmetry. J Cell Biol 1991, 112:225-235. radioresistance and thus might serve as predictive mar- 2. 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MVP and vaults: a role in the radiation response

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Copyright © 2011 by Lara et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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Abstract

Vaults are evolutionary highly conserved ribonucleoproteins particles with a hollow barrel-like structure. The main component of vaults represents the 110 kDa major vault protein (MVP), whereas two minor vaults proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (vPARP) and the 240 kDa telomerase-associated protein-1 (TEP-1). Additionally, at least one small and untranslated RNA is found as a constitutive component. MVP seems to play an important role in the development of multidrug resistance. This particle has also been implicated in the regulation of several cellular processes including transport mechanisms, signal transmission and immune responses. Vaults are considered a prognostic marker for different cancer types. The level of MVP expression predicts the clinical outcome after chemotherapy in different tumour types. Recently, new roles have been assigned to MVP and vaults including the association with the insulin-like growth factor-1, hypoxia-inducible factor-1alpha, and the two major DNA double-strand break repair machineries: non-homologous endjoining and homologous recombination. Furthermore, MVP has been proposed as a useful prognostic factor associated with radiotherapy resistance. Here, we review these novel actions of vaults and discuss a putative role of MVP and vaults in the response to radiotherapy. Keywords: major vault protein, radiotherapy, prognosis, radiation response Review acidic pH, and half vaults can be exchanged to form Major vault protein: an overview of structure and new vaults. Based on these features and on its large composition interior volume, which may encapsulate hundreds of Vaults are ribonucleoprotein particles with a hollow bar- proteins, recent interest in recombinant vaults derives rel-like structure [1] and a mass of 13 MD. In mammals, from nanoparticle research trying to exploit vaults as it is composed of three proteins: MVP (104 kD), the drug delivery system [7,8]. vault poly(adenosine diphosphate-ribose) polymerase Thesequences ofthe2 otherproteins, which are not also known as VPARP (193 kD), and telomerase-asso- part of this shell-like structure and probably reside at ciated protein-1 TEP1 (240 kD), and small untranslated the top center of the caps or within the vaults, are iden- RNA (vRNA) of 141 bases. MVP constitutes more than tified and are present also in the human genome. 70% of the total mass of the complex [2-4], while vARN VPARP presumably ribosylates substrates and TEP1 is represents less than 5% [5]. The molecular architecture important for stabilization of vRNA. Molecular compo- of the rat liver vault complex was recently elucidated at sition of the vault has been roughly estimated as 78-96 high resolution [6]. A vault consists of 2 dimers of half- MVPs, eight VPARPs, two TEP1s, and at least six copies vaults, which align at their waists to form together a of vRNA [9]. Both the high degree of evolutionary con- barrel-like structure with the overall dimensions of 72 × servation and the complex structure of vault particles, as well as its broad distribution in tissues, suggest an 41 × 41 nm. Each half-vault comprises 39 identical major vault proteins (MVP), the major self-assembling important function in cellular processes [10]. Although structural component (Figure 1). Interestingly, vaults vaults have been proposed to play a role in drug resis- can open, the two halves can dissociate at their waists at tance, nucleocytoplasmic transport, and regulation of signaling, a definitive function for MVP or vaults has yet -/- to be assigned as MVP knockout mice (MVP )donot * Correspondence: lhenriquez@dcc.ulpgc.es Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr have phenotypes consistent with these in vitro observa- Negrín. C/Barranco de La Ballena s/n, 35010, Las Palmas de Gran Canaria, tions[11].Thissuggeststhateventhoughthe major Spain -/- component of the vault particle is absent in MVP - Full list of author information is available at the end of the article © 2011 Lara et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lara et al. Radiation Oncology 2011, 6:148 Page 2 of 9 http://www.ro-journal.com/content/6/1/148 to xenobiotics such as bronchial cells and cells lining the intestine [19]. Most of the vaults are located in the cytoplasm, although a small fraction of these particles apparently is also localized at or near the nuclear mem- brane and the nuclear pore complex [20,21]. The wide- spread of vaults in many diverse organisms and cell types suggests that their function is essential to eukaryo- tic cells. Interaction Partners and Putative Functions of Vaults The detailed insight on the structure of MVP and vaults contrasts with the poor understanding of their endogen- ous function. Several observations though indicate that MVP is directly involved in major cytoplasmic signal transduction cascades. In EGF-stimulated cells, tyrosine- Figure 1 Overall structure of the vault shell.Onemoleculeof phosphorylated MVP complexes with the SH2-domain- MVP is colored in tan, and the others are colored in purple. (Left) containing tyrosine phosphatase SHP-2 and interacts Side view of the ribbon representation. The whole vault shell comprises a 78-oligomer polymer of MVP molecules. The size of the with ras-activated downstream kinase Erk, presumably whole particle is ~670 Å from the top to the bottom and ~400 Å in to fine-tune the activity of the Erk-downstream target maximum diameter. The particle has two protruding caps, two Elk-1 [22]. But tyrosine-phosphorylated MVP also binds shoulders, and a body with an invaginated waist. Two half-vaults are to the SH2-domain of Src-kinase and downregulates associated at the waist with N-terminal domains of MVP. (Right) Top view of the ribbon representation. The maximum diameter of the EGF-dependent ERK activation in Src overexpressing cap is ~200 Å. The outer and the inner diameters of the cap-ring cells [23]. Likewise MVP also binds to the tumour sup- are shown. Figure reproduced from Tanaka et al. (2009) with pressor phosphatase and tensin homolog deleted on permission from The American Association for the Advancement of chromosome 10 (PTEN) and a significant quantity of Science (Sciences Magazine). endogenous PTEN associates with vault particles in HeLa cells, thus suggesting a regulatory role for MVP in mice, and vault particles are no longer detected, the the phosphoinositide 3-kinase/Akt (PI 3-kinase/Akt) sig- remaining components TEP1, VPARP, and vRNA might naling pathway [24]. However, MVP-PTEN-interaction still interact and possibly fulfill a functional role. might only be relevant for nuclear import of PTEN The human gene encoding MVP has been located in thereby regulating the nuclear function of PTEN ([25], chromosome 16 (16p11.2) [12], approximately 27 cM see below). Eventually, the identification of the specific proximal to the gene location of the multidrug resis- growth factor-regulated MVP phosphorylation sites and tance protein-1 (MRP1, also designated as ABCC1) [12]. the complexed interaction partner on MVP in response However, although both the ABCC1 and MVP maps to to growth factor stimulation are required to reveal a the short arm of chromosome 16, they are rarely coam- scaffold or direct regulatory function of MVP/vaults on plified and are normally not located within the same these signal transduction cascades. amplicon and can be switched on separately [12,13]. Likewise, a co-immunoprecipitation approach revealed Analysis of the human MVP gene revealed a TATA- that the UV-induced phosphorylation status of MVP less promoter, which also lacks other core-promoter ele- affects the capacity of the constitutive photomorpho- ments but harbors several putative transcription factor genic 1 ubiquitin ligase (COP1) to interact with the binding sites, including an inverted CCAAT box, a p53- transcription factor c-jun. In unstressed cells, cytoplas- binding site, and a GC box element [14]. In silico analy- mic MVP/vault binds to and modifies COP1, presum- sis identified a putative STAT-binding site that strongly ably via the other vault components. Following shuttling resembles an interferon-g-activated site element (GAS), into the nucleus, COP1 complexes with c-jun with high which binds preferentially to STAT1 homodimers [15]. affinity and suppresses its transcriptional activity by tar- Disruption of the STAT-binding site reduces basal MVP geting c-jun for degradation. After UV irradiation, phos- promoter activity, suggesting a role of JAK/STAT signals phorylated MVP does not interact with COP1 anymore, in the activation of MVP expression [16]. With up to eventually leading to the alleviation of COP1-c-jun- 10 particles per cell, vaults are abundantly present in complex formation. Free c-jun subsequently drives AP- many different cell types, although its expression varies 1-controlled gene expression [26]. Negative regulation of among tissues. Vaults are most numerous in macro- downstream signaling has also been identified on the phages [17,18] and epithelial cells with secretory and level of the hypoxia-inducible factor-1a (HIF-1). HIF-1a excretory functions as well as cells chronically exposed and MVP-expression are increased under hypoxia. Lara et al. Radiation Oncology 2011, 6:148 Page 3 of 9 http://www.ro-journal.com/content/6/1/148 However, the stability of HIF-1a protein is enhanced to resistant lung cancer cell line diverting cytostatic drugs higher extents in MVP-knockdown cells. Direct complex from intracellular targets and conferring multidrug resis- formation of vaults with HIF-1a,PHDsand pVHL was tance (MDR) [19]. Several proteins have been linked to demonstrated and suggests that MVP/vault might act as MDR, such as the ABC-drug transporter p-Glycoprotein scaffold protein for ubiquitination and degradation of (P-gp, also designated as ABCB1), members of the mul- HIF1a [27] and thereby affects hypoxia-regulated tidrug resistant protein family (ABCC1, ABCC2, expression of HIF-1a-dependent gene expression. ABCC3), the human breast cancer resistance protein -/- The generation of MVP -mice did not reveal any (BCRP) and the lung-resistance protein (LRP) [36,38,39]. further indications on an essential role of MVP and The LRP was initially discovered due to its high expres- vaults during embryogenesis and in the cellular pro- sion level in a multidrug-resistant but ABCB1-negative cesses in tissues of adult mice under normal environ- lung cancer cell line [19] and has been identified in mental conditions. Furthermore, both embryonic stem 1995 to be the human major vault protein [2]. Thereby, -/- cells and bone marrow cells derived from MVP -mice a first link between the MDR and vaults was established. display a similar sensitivity towards classic cytostatic MVP has been detected in 78% of 61 human cancer agents as their wildtype counterpart cells, and normal cell lines, and its expression levels correlate with resis- tissue toxicity towards doxorubicin in vivo is unchanged tance against a variety of MDR-related and unrelated in the MVP-deficient mice. Interestingly though and drugs [40,41]. Furthermore, upregulation of the MVP unexpectedly identified, MVP and vaults are part of the expression level was determined in multiple human can- effective innate immune response and contribute to the cer cell lines also on treatment with anticancer agents, uptake and clearance of lung pathogens such as Pseudo- including anthracyclins, etoposide and cisplatin, further monas aeruginosa via lipid rafts in lung epithelial cells, supporting a putative link between treatment sensitivity and eventually resistance to lethality [28]. Furthermore, and cellular stress adaptation to cytotoxic agent the activation of MVP-expression by interferon g [19,42-47], and overexpression of MVP is also frequently through the JAK/STAT pathway and enhanced expres- observed at the early steps of resistance selection sion of MVP in macrophages and in dendritic cells sug- [45,46,48,49]. Multiple preclinical studies have corrobo- gest a clear relationship with the immune system rated this link between MDR and the MVP expression [16,29]. However, despite the high abundance of MVP/ level in cancer cells, despite some contradicting studies vaults in MVP-wildtype dendritic cells, no differences in and the fact that the MVP knockout mouse does not dendritic cell migration and antigen presentation and T- show enhanced hypersensitivity to cytostatics. However, -/- cell responses could be observed in MVP -mice. In this might be due to differential cancer to normal cell line treatment sensitivities or the upregulation of other human beings, a strong up-regulation of vault expres- sion during dentritic cell culturing was observed, pro- ABC-transporters or unknown mechanisms of MDR on posing that vaults act as components in the cascade of disruption of functional MVP [11,50]. events regulating dentritic cell effector function [30]. Vaults may mediate multi-drug resistance by the Besides the activation of MVP by interferon, several transport of drugs away from their subcellular targets, other observations indicate that MVP might be involved by the extrusion from the nucleus and/or the sequestra- in immunological responses [31]. It has been reported a tion of drugs into exocytotic vesicles. Either through dramatic induction of vRNA expression in response to these exocytotic vesicles or pump molecules like infection with Epstein-Barr virus [32,33], and vRNA ABCB1, ABCC1, or breast cancer resistance protein at induction has been has been suggested as playing the plasma membrane, the intracellular potency of these important roles in innate immunity [34]. This led to cytotoxic agents will be reduced [51]. Alternatively, the speculate that vRNA/vaults could be involved in anti- two vault-associated VPARP poly(adenosine dipho- viral defence. sphate-ribose) polymerase or TEP-1 may fulfil a protec- Finally, the hollow structure, the rapid movements, the tive function of the genome and thereby contribute to a distinct subcellular localisation (as for example at the drug-resistance profile. Concomitant operation of sev- nuclear membrane), and the in vitro and clinical corre- eral drug resistance mechanisms may often be necessary lations with drug resistance in several types of human to cause the phenotype of MDR, and co-expression of cancers led to the hypothesis that vaults might represent MVP and ABCC1 frequently occurs and associates with rather promiscuous transport vehicles [35-37]. increased drug resistance levels in MDR-selected tumour cells [40]. Interestingly, up-regulation of MVP Drug resistance: the best known role of MVP could be linked in a series of MDR cell lines with a low The MVP has originally been identified as the lung and intermediate level of drug resistance with subse- quent up-regulation of ABCB1 leading to high levels of resistance protein [2]. LRP was discovered almost 20 drug resistance. These findings point the MVP years ago as a protein overexpressed in a multidrug- Lara et al. Radiation Oncology 2011, 6:148 Page 4 of 9 http://www.ro-journal.com/content/6/1/148 expression level as a marker for low level of drug resis- also result in low expression levels of Bax. On the level tance, which is clinically more relevant [19,45,48]. of NHEJ, an inverse correlation between high MVP and Furthermore, several studies reported that the expres- low expression levels of Ku70/80 and pro-apoptotic bax sion of MVP is a predictive marker in several tumour was identified in a cohort of 160 patients with localized types for the response to chemotherapy [52,53]. cervix carcinoma. Interestingly, low Ku70/80 expression Interestingly, human vRNAs produce several small was also associated with upregulated Bcl-2, altered p53, RNAs (svRNAs) by mechanisms different from those in and increased proliferation in this set of patients [59]. Despite the lack of mechanistic insights these data sug- the canonical microRNA (miRNA) pathway. svRNAb gest that overexpression of MVP and vaults might be downregulates CYP3A4, a key enzyme in drug metabo- lism.Thisfinding contributestounderstandthe role of involved in a carcinogenic process with resultant geno- vaults particles in drug resistance, proposing a novel mic instability due to suppressed NHEJ. Though function to vRNAs that may help explain this associa- enhanced proliferative activity, subsequent tumour pro- tion [54]. gression and enhanced treatment resistance requires at the same time an upregulated apoptotic threshold, A novel role for MVP: implications in radiotherapy which might be activated through the suppression of In recent years, several findings indicate a link between Bax, upregulation of Bcl-2, mutated p53-status and MVP and vaults not only to drug-resistance based on its upregulation of the IGF-1R and downstream signalling putative drug-exporter function, but also to DNA- cascades. Eventually, only molecular dissection of the damage and DNA-damage-repair. MVP transcription key signal transduction cascades leading to reduced and protein levels are increased in response to various NHEJ-activity in MVP-overexpressing and MVP- DNA-damaging agents, including ionizing radiation (IR) depleted cells will elucidate the association between [55]. Interestingly, VPARP and, to lesser extent, TEP-1- MVP/vaults, NHEJ and a deregulated apoptotic thresh- deficient mice, have an increased incidence of carcino- old. Moreover, MVP increases with age both in vitro gen-induced colon tumours [56]. These findings indicate andinvivo,andthatage-related upregulation of MVP that vaults may play a role in facilitating DNA repair facilitates apoptosis resistance of senescent human processes. diploid fibroblasts based on the interaction with c-Jun- The high cytotoxicity of IR is mainly based on its abil- mediated downregulation of BCL-2 [60]. Thus, MVP is itytoinduceDNA double strand breaks (DSB)via gen- suggested to be playing an important role in the resis- eration of reactive oxygen species. DSB can be repaired tance of senescent fibroblasts to apoptosis by modula- tion of BCL-2 expression by JNK pathway, regulating by the two major DSB repair machineries: homologous recombination (HR) and non-homologous end joining cellular signaling and survival and being a potential (NHEJ). The fact that error-free repair by HR depends therapeutic target for modulation of resistance to apop- on thepresenceofan intactsister chromatid restricts tosis implicated in aging modulation and cancer treat- this pathway to occur during S and G2 phases of the ment [61]. cell cycle. This is, in contrast to error-prone repair by A novel link between the intracellular level of MVP NHEJ which can function throughout the cell cycle and and homologous recombination, the second DNA-DSB- is therefore thought to be the predominant DSB repair repair machinery, has recently been identified as part of pathway in mammalian cells. On the other hand, HR the cellular stress response to ionizing radiation (Pre- represents the more interesting target to sensitize speci- sented in ESTRO 29; S 51, 129 oral). MVP-depleted fically tumor cells to DNA damaging agents leading to tumour cells are more radiosensitive than their wildtype an enhanced therapeutic window. cognate cells, probably due to direct interference with MVP and vaults have recently been linked to both homologous recombination. In comparison to control major DSB-machineries. Ku70 and Ku80 are key pro- cells, Rad51-foci are strongly reduced in irradiated but teinsinNHEJ, andalsoplayastrongregulatoryrolein MVP-depleted cells and thus vaults may coordinate cor- apoptosis through Bax/Bcl-2 interactions [57,58]. The rect HR-complex formation at the site of the DSB. DNA end-joining protein Ku70 inhibits apoptosis by Vaults might also guarantee sufficient protein level of sequestering Bax away from the mitochondria. However, Rad51 required for homologous recombination via coor- newly synthesized Bax undergoes ubiquitination, which dinated Rad51 expression. It has been reported that negatively regulates its proapoptotic function by labeling MVP mediates nuclear import of PTEN and regulates it for proteasomal degradation. Interestingly, ubiquiti- its nuclear function [24,62]. Nuclear PTEN expression is high in untransformed cells but decreases with tumour nated Bax associates with Ku70, which mediates Bax progression. While cytoplasmic PTEN inhibits the phos- deubiquitination, simultaneously generating the active phoinositol-3-kinase (PI3K)/AKT pathway, nuclear form of Bax but sequestered away from the mitochon- dria [57]. Low expression level of Ku70 might therefore PTEN inhibits phosphorylation of MAPK and Lara et al. Radiation Oncology 2011, 6:148 Page 5 of 9 http://www.ro-journal.com/content/6/1/148 consequently reduces the expression of cyclin D leading Table 1 Clinical studies investigating the association between MVP and therapy response and survival to a G0/G1 cell cycle arrest. Though, PTEN also acts as cofactor for the transcription factor E2F1, driving Author Patients (n) Tumour Response DFS OS expression of RAD51. Cells deficient in PTEN have Izquierdo [13] 57 Ovarian cancer Yes Yes Yes reduced capacity of homologous recombination-depen- Schadendorf [90] 71 Melanoma Yes dent DNA repair, most probably due to reduced levels Ramani [95] 21 Neuroblastoma No of RAD51. Thereby, PTEN is also important for the Dingemans [96] 36 NSCLC No No maintenance of chromosomal stability reducing the inci- Linn [97] 70 Breast cancer No dence of spontaneous double strand breaks. Interest- Uozaki [98] 60 Osteosarcoma Yes Yes ingly, loss of PTEN in tumour cells and concomitantly Arts [81] 115 Ovarian cancer No No No reduced homologous recombination can thereby be Pohl [99] 99 Breast cancer No No No exploited by the inhibiton of PARP, creating a situation Volm [100] 87 NSCLC Yes No of synthetic lethality [63,64]. Since MVP and vaults are Goff [101] 29 Ovarian cancer No involved in nuclear import of PTEN and homologous Pohl [102] 68 Colorrecto No recombination, it will be of interest to determine Diestra [89] 83 Bladder cancer Yes whether the MVP expression level also affects genomic Harada [103] 57 NSCLC Yes instability and sensitivity to PARP-inhibition. Silva [93] 78 HNSCC Yes Yes Despite the fact that we have so far only limited DFS, disease-free survival; OS, overall survival; NSCLC, non-small cell lung insights into the mechanisms how MVP and vault inter- cancer; HNSCC, head-and-neck squamous cell carcinoma. act with the two double strand-break repair machineries, these results indicate that MVP and vaults may co-regu- type of malignancy is still questionable, and standardized late correct DNA repair of spontaneous and treatment- detection methods are needed. Nevertheless, a direct induced double strand breaks. Due to the barrel-like association between MVP expression and therapy resis- structure vaults may act as carriers not only for toxic tance and prognosis in patients suffering from acute agents but also for the coordinated intracellular trans- myeloid leukaemia was identified [67-70]. A positive port of DNA-repair related proteins and thereby act as correlation between MVP expression and worse patient scaffold protein or shuttling vector. Otherwise, the prognosis, therapy response, and survival rate has been vaults associated proteins VPARP or TEP1 might play a reported in acute lymphoblastic leukaemia patients so far not-identified role for correct DNA repair, which [71-73], and similar results have been described in adult could only be achieved as part of an intact vaults. As T-cell leukaemia [74,75] and multiple myeloma [76-78]. indicated above, in vitro studies revealed that gene On the other hand, relatively few studies have expression levels of MDR-related proteins increased addressed the role of MVP in solid tumours, with con- after fractionated irradiation. It is well known that radia- tradictory findings. Thus, the quality of MVP as prog- tion treatment can induce resistance to various cytotoxic nostic marker in ovarian carcinoma is unclear so far, drugs [65], although the molecular basis of this interac- with positive [79,80] and negative [81,82] associations tion are complex. Irradiated cell lines showed a signifi- reported. Result regarding to breast cancer [83,84], non- cant resistance to cisplatin, doxorubicin and small cell lung cancer [85,86], or different types of sar- bendamustine, suggesting a novel mechanism in the comas are inconclusive [87,88]. On the other hand, appearance of MDR, which might involve a radiation- MVP has been established as a reliable factor for induced increment of LRP/MVP [66]. response to chemotherapy in bladder cancer patients [89], melanoma [90], and determining the aggressive MVP and tumour malignancies: vaults as a predictive/ phenotype of testicular germ-cell tumours [91] and glio- prognostic marker blastoma [92]. Numerous studies were performed to clarify the expres- With regard to a putative role of MVP in radiation sion status of MVP in human malignancies as a predic- resistance, it has been reported that MVP expression is tive and prognostic marker for the chemotherapy strongly associated with local-disease free survival and response and patient prognosis (Table 1). These studies cancer-specific survival in a series of patients suffering mainly focused on haematological malignancies. The from squamous cell carcinoma of the oropharynx who results should be viewed with caution, since they will be received primary radiotherapy with curative intent (in influenced by factors such as 1) MVP detection assays univariate and multivariate analyses) [93]. Elevated MVP (especially referred to gene expression), 2) number of expression seems to be associated with a RT-resistant patients included, or 3) type of statistical analysis per- subset of patients, proposing MVP as a novel useful formed (univariate vs. multivariate analysis). The quality prognostic marker associated with RT [93]. The under- of MVP as a prognostic or predictive marker in this lying mechanisms behind this association are not well Lara et al. Radiation Oncology 2011, 6:148 Page 6 of 9 http://www.ro-journal.com/content/6/1/148 List of abbreviations defined today but might be linked to the above cited HIF-1: hypoxia-inducible factor-1; HR: homologous recombination; MDR: role of MVP in DNA repair and apoptotic threshold. multidrug resistance; MRP: multidrug resistance protein; MVP: major vaults The complexity but also interest in MVP as a predictive protein; NHEJ: non-homologous end joining; RT: radiotherapy; TEP-1: telomerase-associated protein-1; VPARP: vault poly(adenosine diphosphate- and/or prognostic marker is also illustrated in cervical ribose) polymerase. cancer patients receiving combined radiochemotherapy [52]. Increased MVP and IGF-1R expression levels were Acknowledgements We thank Professor Adrian Begg for helpful comments during the related to a small cohort of cervical cancer patients with preparation of this manuscript. reduced long-term local control, in patients who other- wise achieved clinical complete response to radioche- Author details Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr motherapy. High MVP expression was strongly related to Negrín. C/Barranco de La Ballena s/n, 35010, Las Palmas de Gran Canaria, high IGF1-R expression, which is associated with chemo- Spain. Clinical Sciences Department, Universidad de Las Palmas de Gran and radioresistance in localized cervical carcinoma Canaria. C/Dr. Pasteur s/n, 35016, Las Palmas de Gran Canaria, Spain. Instituto Canario de Investigación del Cáncer, Canary Islands, Spain. patients [94]. This association suggests that both proteins Radiation Oncology Department, University Hospital Zürich. Raemistrasse need to be expressed to confer chemoradioresistance in 100CH-8091, Zürich, Switzerland. cervical cancer. This was further supported by a sub- Authors’ contributions group of patients who showed low levels of MVP and PCL has been involved in revising the manuscript critically for important IGF1R and who presented excellent survival rates once intellectual content and has given final approval of the version to be [52]. All of the responding patients with negative or fairly published, MP has been involved in drafting the manuscript and has made substantial contributions to conception and design, MZ has made positive (low MVP) tumours were free of local, distant or substantial contributions to conception and design, LAHH has been involved death related disease. These results were similar to the in drafting the manuscript and has made substantial contributions to ones previously obtained for IGF-1R as a prognostic mar- conception and design. All authors read and approved the final manuscript. ker [94]. Combination analysis was performed grouping Competing interests MVP and IGF-1R expression in tumours, showing that The authors declare that they have no competing interests. all responding patients withlow MVP/IGF-1R tumours Received: 3 August 2011 Accepted: 31 October 2011 were free of local disease, relapse or death related disease. Published: 31 October 2011 As illustrated by these studies, we are still far away to have identified a mechanistic link between MVP expres- References sion level and treatment response, and it is still a matter 1. Kedersha NL, Heuser JE, Chugani DC, Rome LH: Vaults. III. Vault ribonucleoprotein particles open into flower-like structures with of debate in how far vaults are involved in chemo- and octagonal symmetry. J Cell Biol 1991, 112:225-235. radioresistance and thus might serve as predictive mar- 2. 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Journal

Radiation OncologySpringer Journals

Published: Oct 31, 2011

References