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Prolyl isomerase Pin1 and neurotrophins: a loop that may determine the fate of cells in cancer and neurodegeneration:

Prolyl isomerase Pin1 and neurotrophins: a loop that may determine the fate of cells in cancer... 665776 TAM0010.1177/1758834016665776Therapeutic Advances in Medical OncologyF Angelucci and J Hort research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Prolyl isomerase Pin1 and neurotrophins: 2017, Vol. 9(1) 59 –62 DOI: 10.1177/ a loop that may determine the fate of cells © The Author(s), 2016. Reprints and permissions: in cancer and neurodegeneration http://www.sagepub.co.uk/ journalsPermissions.nav Francesco Angelucci and Jakub Hort Abstract: Increased survival, differentiation, and apoptotic death are common mechanisms relevant for both cancer and neurodegenerative diseases. Although these disorders are characterized by different manifestations, it appears that a common mechanism may be present which directs the fate of a cell to either degeneration or proliferation. There are two classes of proteins that have been extensively investigated in these diseases but their possible interaction during signal transduction has not been studied. Prolyl isomerase Pin1 is an enzyme which translates Ser/Thr-Pro phosphorylation into conformational changes able to modify the activities of its substrates. Its role in cancer development has been linked to its capacity to induce conformational changes to the tumor suppressor gene p53. Neurotrophins belong to a family of proteins that induce opposite effects on neuronal cells such as increased survival, development, and function. According to their function, alteration of these proteins during neurodegenerative processes has been investigated and reported in a number of experimental paradigms involving animal models and humans. However, in recent years, it has been shown that Pin1 downregulation is present in neurodegenerative disorders, while increased expression of neurotrophins and their receptors is found in certain types of cancer and correlate with poor prognosis. Notably, at the level of signal transduction, Pin1 and neurotrophin activity regulate the outcome of similar pathways such as proline-directed kinase and, most importantly, p53 signaling. Thus the possible existence of a loop between Pin1 and neurotrophins was investigated to understand the pathogenesis of these diseases. Keywords: cancer, neurodegeneration, neurotrophins, p53, Pin1 Introduction proline [Lu and Zhou, 2007]. Pin1 has been iden- Recent epidemiological studies have shown an tified as a regulator of phosphorylation signaling inverse association between the occurrence of in several types of cancer, including breast, gas- cancer and Alzheimer’s disease (AD) [Ma et  al. tric, lung, esophageal, head and neck squamous Correspondence to: Francesco Angelucci, PhD 2014; Musicco et  al. 2013], supporting the idea cell carcinoma, and laryngeal squamous cell can- Department of Clinical that a common mechanism may be present and cer. In these types of cancer, Pin1 is either over and Behavioral Neurology, IRCCS Santa Lucia directs the fate of a cell to either degeneration or expressed or present with genetic variants in the Foundation, 00179, Rome, proliferation. Nevertheless, so far this mechanism Pin1 gene [Finn and Lu, 2008]. This promoting Italy f.angelucci@hsantalucia.it has not been discovered. action of Pin1 in cancer has also been associated Jakub Hort, MD, PhD with its capacity to inhibit some tumor suppressor Memory Clinic, Department of Neurology, genes, such as RUNX3 and p53 [Hu and Wulf, 2nd Faculty of Medicine, The prolyl isomerase Pin1 in cancer and 2011; Nicole Tsang et al. 2013]. While in normal Charles University in Prague and Motol Alzheimer’s disease conditions Pin1 promotes the activity of onco- University Hospital, Prolyl isomerase Pin1 is a unique enzyme that genes such as p53, in pathological conditions this Prague, and International Clinical Research Center, changes the shape of target proteins by acting on regulatory mechanism accelerates malignant St Anne’s University specific amino acids that have been phosphoryl- transformation when the oncogene carries a domi- Hospital Brno, Brno, Czech Republic ated; serine or threonine residues that precede nant negative mutation [Hu and Wulf, 2011]. http://tam.sagepub.com 59 Therapeutic Advances in Medical Oncology 9(1) Interestingly, it has been shown that Pin1 altera- adapts to a new situation in its environment. In tions are also present in pathologies character- humans, postmortem studies have shown that ized by neurodegenerative processes such as AD neurotrophin brain levels are reduced in AD, sup- [Pastorino et  al. 2012]. This field of research is porting the notion that these proteins are neuro- still ongoing but present evidence shows that protective and may have a potential role in the there is a downregulation in the expression of treatment of neurodegenerative disorders. Pin1 in neurons and that this event may be part of the pathogenic mechanism in AD. Although Neurotrophin signaling through the Trk recep- its role in neurons is still unclear, Pin1 is known tor mainly induces three intracellular signaling to regulate a number of important proteins, pathways: inhibition of programmed cell death including tau and amyloid precursor (APP) pro- (apoptosis), induction of growth arrest, and pro- teins. In contrast to cycling cells, neuronal motion of neurogenesis. Interestingly, in recent expression of Pin 1 increases during differentia- years it has become evident that the survival- tion and remains elevated throughout the lifes- promoting action of neurotrophins may sustain pan [Liou et al. 2003]. Moreover, overexpression certain types of cancer. There are several reasons of Pin1 in mature neurons protects against neu- why neurotrophins can also play a role in cancer. rodegeneration induced by tau overexpression First of all, the Trk receptor was first described [Lim et al. 2008]. Pin1 knockout mice develop a as proto-oncogene and the receptor for NGF premature age-dependent neurodegeneration TrkA was found to be downregulated in neuro- similar to AD in humans characterized by tau blastoma with aggressive behavior [Nakagawara hyperphosphorylation and an increase in the et  al. 1993], suggesting that this kind of tumor pathogenic processing of APP [Liou et al. 2003; may require the presence of NGF for survival Pastorino et al. 2006]. and may regress in its absence. This concept has been further developed leading to the hypothesis These studies indicate that Pin1 activity has a that the Trk receptor system may represent a dual role in cells. It may favor proliferation or bridge between cancer and neuronal develop- induce cell death depending on the circum- ment in brain tumors such as neuroblastoma stances, which may include multiple mechanisms, and medulloblastoma [Nakagawara, 2001]. such as gene transcription and protein phospho- Furthermore, the involvement of NGF, BDNF, rylation. Pin1 can thus serve as a molecular NT-4/5 and their receptors has been demon- ‘timer’ or ‘switch’, turning proteins or entire strated in other types of cancer, such as breast pathways ‘on’ or ‘off’ at critical times. and lung cancer. Notably in these tumors, in vitro and in vivo experiments have shown that stimulation of neurotrophin and the Trk recep- Neurotrophins in cancer and Alzheimer’s tors can result in cellular growth [Nakagawara, disease 2001; Sinkevicius et  al. 2014], while preclinical There is another class of protein which resembles studies demonstrated that targeting neurotro- the action of Pin1 at cellular level. These pro- phins and/or their receptors induces an inhibi- teins, named neurotrophins, play a pivotal role in tion of cancer cell survival, proliferation, and cell survival, and the development and function of invasion [Hondermarck, 2012]. the neurons. The neurotrophin family includes at least four members: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neu- Signal transduction rotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Summarizing the experimental evidence The action of neurotrophins is mediated by bind- reported, it appears that the pattern of changes ing to the tyrosine kinase (Trk) family of recep- in neurotrophin and Pin1 expressions in cancer tors (including TrkA, TrkB, and TrkC), and to and neurodegeneration are comparable. the p75 receptor (p75NTR), a member of the Accordingly, tentative explanations for AD– tumor necrosis factor receptor family [Huang and cancer ‘inverse comorbidity’ have been proposed Reichardt, 2001]. with both Pin1 [Driver et  al. 2015] and neuro- trophin dysregulation [Krüttgen et  al. 2006]. Neurotrophins not only regulate the survival of The possible relationship between neurotro- neurons undergoing neurodegeneration in AD, phins and Pin1 can be depicted further by ana- but also (in the case of BDNF) synaptic plasticity, lyzing the signal transduction pathways activated the process through which a neuron responds and by these proteins. Neurotrophins and Pin1 share 60 http://tam.sagepub.com F Angelucci and J Hort important mechanisms in cells. During their sur- Moreover, Pin1 has a central role in transducing vival-promoting activity, neurotrophins and phosphorylation of p53 into conformational Pin1 may activate proline-directed kinase signal- changes that affect p53 stability and function. p53 ing and consequently regulate cell proliferation is not only a tumor suppressor but it integrates a and survival. These pathways include mitogen- number of extracellular signals that involve neuro- activated protein kinases, nuclear factor kappa- trophins. For example, p53 gene silencing or dom- light-chain-enhancer of activated B cells, inant negative forms of p53 that inhibit p53 glycogen synthase kinase 3, and others. Also, transactivation capacity block NGF-dependent during their apoptotic promoting action, similar neurite outgrowth in PC-12 cells, thereby showing pathways can be activated, such as c-Jun a direct requirement for p53 in neuronal differen- N-terminal kinase. In addition, neurotrophins tiation and outgrowth. Thus p53 is necessary for and Pin1 can both influence the expression of the action of neurotrophins and may contribute to p53, which is considered to be a tumor suppres- neuronal development through the regulation of sor but it has also been proposed that it has a gene targets distinct from its known transcriptional novel role in neuronal differentiation, axon guid- targets for apoptosis or DNA repair [Brynczka ance, neurite outgrowth, and axonal regenera- et al. 2007]. Given its role in regulating p53 con- tion [Tedeschi and Di Giovanni, 2009]. formational changes, Pin1 may be the factor that can drive p53 to be responsive to the action of neu- rotrophins during either cancer or neurodegenera- Pin1 and neurotrophins tive processes. When Pin1 is overexpressed in Pin1 and neurotrophins may act synergistically cancer, it may stimulate the Trk receptor-mediated and determine the fate of cells with regard to neu- pathways of neurotrophins and, at the same time, ronal survival or neuronal death, and this mecha- induce conformational changes of p53 in its sur- nism is may be part of the pathogenic mechanism vival-promoting direction. On the other hand, dur- connecting cancer and neurodegenerative disor- ing neurodegenerative processes, low expression of ders, at least AD. Going further, we suggest that Pin1 may be the cause of reduced functionality of Pin1 might be required for the signal transduc- the neurotrophin–Trk system and p53 survival tion pathways activated by Trk receptors, thus action, with the result of favoring neuronal death. modulating neurotrophin activity. A possible scenario(s) on how Pin1 affects neu- Possible physiologic and therapeutic rotrophin activity is now described. As stated implications before, Pin1 is the only known isomerase that If inhibition or stimulation of Pin1 may cause an specifically catalyzes the phosphorylated pThr/ alteration in neurotrophins or their receptor levels pSer-Pro motifs from cis-configuration to trans- and/or their functionality, this may introduce the configuration. Induction of serine/threonine possibility of modulating these proteins epigeneti- kinase activity is critical for cell survival and pro- cally and not by exogenous administration, the liferation, and is part of the signal transduction method investigated most so far. The fact that cascade of neurotrophins. Specifically, among epigenetic mechanisms, such those regulated by the pathways activated by neurotrophins through Pin1, are reversible as opposed to genetic modifi- the Trk receptors, a survival pathway includes cation, is even more intriguing. Nonetheless, it is the activation of the serine/threonine protein clear that the loop between Pin1 and neurotro- kinase B (also known as Akt). phin needs to be in equilibrium, otherwise favor- ing one (cancer) or the other (neurodegenerative Akt plays an essential role in cell survival, growth, disorders) pathological process. migration, and proliferation, Altered Akt activity has been associated with cancer and other disease Funding conditions, including neurodegenerative diseases. The author(s) received no financial support for Recent reports have shown that the stability of the research, authorship, and/or publication of Akt protein is regulated through phosphorylation this article. on its Thr-Pro motifs and that Pin1 is a crucial factor for Akt stability and activation phospho- Conflict of interest statement rylation [Liao et  al. 2009]. By this mechanism The author(s) declared no potential conflicts of Pin1 can be a molecular ‘timer’ or ‘switch’, turn- interest with respect to the research, authorship, ing neurotrophin pathways ‘on’ or ‘off’. and/or publication of this article. http://tam.sagepub.com 61 Therapeutic Advances in Medical Oncology 9(1) signalling and disease. Nat Rev Mol Cell Biol 8: References 904–916. Brynczka, C., Labhart, P. and Merrick, B. (2007) NGF-mediated transcriptional targets of p53 in PC12 Ma, L., Yu, J., Wang, H., Meng, X., Tan, C., Wang, neuronal differentiation. BMC Genomics 8: 139. C. et al. (2014) Association between cancer and Alzheimer’s disease: systematic review and meta- Driver, J., Zhou, X. and Lu, K. (2015) Pin1 analysis. J Alzheimers Dis 42: 565–573. dysregulation helps to explain the inverse association between cancer and Alzheimer’s disease. Biochim Musicco, M., Adorni, F., Di Santo, S., Prinelli, F., Biophys Acta 1850: 2069–2076. Pettenati, C., Caltagirone, C. et al. (2013) Inverse occurrence of cancer and Alzheimer disease: a Finn, G. and Lu, K. (2008) Phosphorylation-specific population-based incidence study. Neurology 81: prolyl isomerase Pin1 as a new diagnostic and 322–328. therapeutic target for cancer. Curr Cancer Drug Targets 8: 223–229. Nakagawara, A. (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Hondermarck, H. (2012) Neurotrophins and their Cancer Lett 169: 107–114. receptors in breast cancer. Cytokine Growth Factor Rev 23: 357–365. Nakagawara, A., Arima-Nakagawara, M., Scavarda, N., Azar, C., Cantor, A. and Brodeur, G. (1993) Hu, H. and Wulf, G. (2011) The amplifier effect: how Association between high levels of expression of Pin1 empowers mutant p53. Breast Cancer Res 13: the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 328: 847–854. Huang, E. and Reichardt, L. (2001) Neurotrophins: Nicole Tsang, Y., Wu, X., Lim, J., Wee Ong, C., roles in neuronal development and function. Annu Salto-Tellez, M., Ito, K. et al. (2013) Prolyl isomerase Rev Neurosci 24: 677–736. Pin1 downregulates tumor suppressor RUNX3 in Krüttgen, A., Schneider, I. and Weis, J. (2006) breast cancer. Oncogene 32: 1488–1496. The dark side of the NGF family: neurotrophins in Pastorino, L., Ma, S., Balastik, M., Huang, P., neoplasias. Brain Pathol 16: 304–310. Pandya, D., Nicholson, L. et al. (2012) Alzheimer’s Liao, Y., Wei, Y., Zhou, X., Yang, J., Dai, C., Chen, disease-related loss of Pin1 function influences the Y. et al. (2009) Peptidyl-prolyl cis/trans isomerase Pin1 intracellular localization and the processing of AβPP. is critical for the regulation of PKB/Akt stability and J Alzheimers Dis 30: 277–297. activation phosphorylation. Oncogene 28: 2436–2445. Pastorino, L., Sun, A., Lu, P., Zhou, X., Balastik, Lim, J., Balastik, M., Lee, T., Nakamura, K., Liou, M., Finn, G. et al. (2006) The prolyl isomerase Pin1 Y., Sun, A. et al. (2008) Pin1 has opposite effects on regulates amyloid precursor protein processing and wild-type and P301L tau stability and tauopathy. J amyloid-beta production. Nature 440: 528–534. Clin Invest 118: 1877–1889. Sinkevicius, K., Kriegel, C., Bellaria, K., Lee, J., Lau, Liou, Y., Sun, A., Ryo, A., Zhou, X., Yu, Z., Huang, A., Leeman, K. et al. (2014) Neurotrophin receptor H. et al. (2003) Role of the prolyl isomerase Pin1 in TrkB promotes lung adenocarcinoma metastasis. Proc protecting against age-dependent neurodegeneration. Natl Acad Sci USA 111: 10299–10304. Nature 424: 556–561. Visit SAGE journals online Tedeschi, A. and Di Giovanni, S. (2009) The non- http://tam.sagepub.com Lu, K. and Zhou, X. (2007) The prolyl isomerase apoptotic role of p53 in neuronal biology: enlightening PIN1: a pivotal new twist in phosphorylation SAGE journals the dark side of the moon. EMBO Rep 10: 576–583. 62 http://tam.sagepub.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

Prolyl isomerase Pin1 and neurotrophins: a loop that may determine the fate of cells in cancer and neurodegeneration:

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665776 TAM0010.1177/1758834016665776Therapeutic Advances in Medical OncologyF Angelucci and J Hort research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Prolyl isomerase Pin1 and neurotrophins: 2017, Vol. 9(1) 59 –62 DOI: 10.1177/ a loop that may determine the fate of cells © The Author(s), 2016. Reprints and permissions: in cancer and neurodegeneration http://www.sagepub.co.uk/ journalsPermissions.nav Francesco Angelucci and Jakub Hort Abstract: Increased survival, differentiation, and apoptotic death are common mechanisms relevant for both cancer and neurodegenerative diseases. Although these disorders are characterized by different manifestations, it appears that a common mechanism may be present which directs the fate of a cell to either degeneration or proliferation. There are two classes of proteins that have been extensively investigated in these diseases but their possible interaction during signal transduction has not been studied. Prolyl isomerase Pin1 is an enzyme which translates Ser/Thr-Pro phosphorylation into conformational changes able to modify the activities of its substrates. Its role in cancer development has been linked to its capacity to induce conformational changes to the tumor suppressor gene p53. Neurotrophins belong to a family of proteins that induce opposite effects on neuronal cells such as increased survival, development, and function. According to their function, alteration of these proteins during neurodegenerative processes has been investigated and reported in a number of experimental paradigms involving animal models and humans. However, in recent years, it has been shown that Pin1 downregulation is present in neurodegenerative disorders, while increased expression of neurotrophins and their receptors is found in certain types of cancer and correlate with poor prognosis. Notably, at the level of signal transduction, Pin1 and neurotrophin activity regulate the outcome of similar pathways such as proline-directed kinase and, most importantly, p53 signaling. Thus the possible existence of a loop between Pin1 and neurotrophins was investigated to understand the pathogenesis of these diseases. Keywords: cancer, neurodegeneration, neurotrophins, p53, Pin1 Introduction proline [Lu and Zhou, 2007]. Pin1 has been iden- Recent epidemiological studies have shown an tified as a regulator of phosphorylation signaling inverse association between the occurrence of in several types of cancer, including breast, gas- cancer and Alzheimer’s disease (AD) [Ma et  al. tric, lung, esophageal, head and neck squamous Correspondence to: Francesco Angelucci, PhD 2014; Musicco et  al. 2013], supporting the idea cell carcinoma, and laryngeal squamous cell can- Department of Clinical that a common mechanism may be present and cer. In these types of cancer, Pin1 is either over and Behavioral Neurology, IRCCS Santa Lucia directs the fate of a cell to either degeneration or expressed or present with genetic variants in the Foundation, 00179, Rome, proliferation. Nevertheless, so far this mechanism Pin1 gene [Finn and Lu, 2008]. This promoting Italy f.angelucci@hsantalucia.it has not been discovered. action of Pin1 in cancer has also been associated Jakub Hort, MD, PhD with its capacity to inhibit some tumor suppressor Memory Clinic, Department of Neurology, genes, such as RUNX3 and p53 [Hu and Wulf, 2nd Faculty of Medicine, The prolyl isomerase Pin1 in cancer and 2011; Nicole Tsang et al. 2013]. While in normal Charles University in Prague and Motol Alzheimer’s disease conditions Pin1 promotes the activity of onco- University Hospital, Prolyl isomerase Pin1 is a unique enzyme that genes such as p53, in pathological conditions this Prague, and International Clinical Research Center, changes the shape of target proteins by acting on regulatory mechanism accelerates malignant St Anne’s University specific amino acids that have been phosphoryl- transformation when the oncogene carries a domi- Hospital Brno, Brno, Czech Republic ated; serine or threonine residues that precede nant negative mutation [Hu and Wulf, 2011]. http://tam.sagepub.com 59 Therapeutic Advances in Medical Oncology 9(1) Interestingly, it has been shown that Pin1 altera- adapts to a new situation in its environment. In tions are also present in pathologies character- humans, postmortem studies have shown that ized by neurodegenerative processes such as AD neurotrophin brain levels are reduced in AD, sup- [Pastorino et  al. 2012]. This field of research is porting the notion that these proteins are neuro- still ongoing but present evidence shows that protective and may have a potential role in the there is a downregulation in the expression of treatment of neurodegenerative disorders. Pin1 in neurons and that this event may be part of the pathogenic mechanism in AD. Although Neurotrophin signaling through the Trk recep- its role in neurons is still unclear, Pin1 is known tor mainly induces three intracellular signaling to regulate a number of important proteins, pathways: inhibition of programmed cell death including tau and amyloid precursor (APP) pro- (apoptosis), induction of growth arrest, and pro- teins. In contrast to cycling cells, neuronal motion of neurogenesis. Interestingly, in recent expression of Pin 1 increases during differentia- years it has become evident that the survival- tion and remains elevated throughout the lifes- promoting action of neurotrophins may sustain pan [Liou et al. 2003]. Moreover, overexpression certain types of cancer. There are several reasons of Pin1 in mature neurons protects against neu- why neurotrophins can also play a role in cancer. rodegeneration induced by tau overexpression First of all, the Trk receptor was first described [Lim et al. 2008]. Pin1 knockout mice develop a as proto-oncogene and the receptor for NGF premature age-dependent neurodegeneration TrkA was found to be downregulated in neuro- similar to AD in humans characterized by tau blastoma with aggressive behavior [Nakagawara hyperphosphorylation and an increase in the et  al. 1993], suggesting that this kind of tumor pathogenic processing of APP [Liou et al. 2003; may require the presence of NGF for survival Pastorino et al. 2006]. and may regress in its absence. This concept has been further developed leading to the hypothesis These studies indicate that Pin1 activity has a that the Trk receptor system may represent a dual role in cells. It may favor proliferation or bridge between cancer and neuronal develop- induce cell death depending on the circum- ment in brain tumors such as neuroblastoma stances, which may include multiple mechanisms, and medulloblastoma [Nakagawara, 2001]. such as gene transcription and protein phospho- Furthermore, the involvement of NGF, BDNF, rylation. Pin1 can thus serve as a molecular NT-4/5 and their receptors has been demon- ‘timer’ or ‘switch’, turning proteins or entire strated in other types of cancer, such as breast pathways ‘on’ or ‘off’ at critical times. and lung cancer. Notably in these tumors, in vitro and in vivo experiments have shown that stimulation of neurotrophin and the Trk recep- Neurotrophins in cancer and Alzheimer’s tors can result in cellular growth [Nakagawara, disease 2001; Sinkevicius et  al. 2014], while preclinical There is another class of protein which resembles studies demonstrated that targeting neurotro- the action of Pin1 at cellular level. These pro- phins and/or their receptors induces an inhibi- teins, named neurotrophins, play a pivotal role in tion of cancer cell survival, proliferation, and cell survival, and the development and function of invasion [Hondermarck, 2012]. the neurons. The neurotrophin family includes at least four members: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neu- Signal transduction rotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Summarizing the experimental evidence The action of neurotrophins is mediated by bind- reported, it appears that the pattern of changes ing to the tyrosine kinase (Trk) family of recep- in neurotrophin and Pin1 expressions in cancer tors (including TrkA, TrkB, and TrkC), and to and neurodegeneration are comparable. the p75 receptor (p75NTR), a member of the Accordingly, tentative explanations for AD– tumor necrosis factor receptor family [Huang and cancer ‘inverse comorbidity’ have been proposed Reichardt, 2001]. with both Pin1 [Driver et  al. 2015] and neuro- trophin dysregulation [Krüttgen et  al. 2006]. Neurotrophins not only regulate the survival of The possible relationship between neurotro- neurons undergoing neurodegeneration in AD, phins and Pin1 can be depicted further by ana- but also (in the case of BDNF) synaptic plasticity, lyzing the signal transduction pathways activated the process through which a neuron responds and by these proteins. Neurotrophins and Pin1 share 60 http://tam.sagepub.com F Angelucci and J Hort important mechanisms in cells. During their sur- Moreover, Pin1 has a central role in transducing vival-promoting activity, neurotrophins and phosphorylation of p53 into conformational Pin1 may activate proline-directed kinase signal- changes that affect p53 stability and function. p53 ing and consequently regulate cell proliferation is not only a tumor suppressor but it integrates a and survival. These pathways include mitogen- number of extracellular signals that involve neuro- activated protein kinases, nuclear factor kappa- trophins. For example, p53 gene silencing or dom- light-chain-enhancer of activated B cells, inant negative forms of p53 that inhibit p53 glycogen synthase kinase 3, and others. Also, transactivation capacity block NGF-dependent during their apoptotic promoting action, similar neurite outgrowth in PC-12 cells, thereby showing pathways can be activated, such as c-Jun a direct requirement for p53 in neuronal differen- N-terminal kinase. In addition, neurotrophins tiation and outgrowth. Thus p53 is necessary for and Pin1 can both influence the expression of the action of neurotrophins and may contribute to p53, which is considered to be a tumor suppres- neuronal development through the regulation of sor but it has also been proposed that it has a gene targets distinct from its known transcriptional novel role in neuronal differentiation, axon guid- targets for apoptosis or DNA repair [Brynczka ance, neurite outgrowth, and axonal regenera- et al. 2007]. Given its role in regulating p53 con- tion [Tedeschi and Di Giovanni, 2009]. formational changes, Pin1 may be the factor that can drive p53 to be responsive to the action of neu- rotrophins during either cancer or neurodegenera- Pin1 and neurotrophins tive processes. When Pin1 is overexpressed in Pin1 and neurotrophins may act synergistically cancer, it may stimulate the Trk receptor-mediated and determine the fate of cells with regard to neu- pathways of neurotrophins and, at the same time, ronal survival or neuronal death, and this mecha- induce conformational changes of p53 in its sur- nism is may be part of the pathogenic mechanism vival-promoting direction. On the other hand, dur- connecting cancer and neurodegenerative disor- ing neurodegenerative processes, low expression of ders, at least AD. Going further, we suggest that Pin1 may be the cause of reduced functionality of Pin1 might be required for the signal transduc- the neurotrophin–Trk system and p53 survival tion pathways activated by Trk receptors, thus action, with the result of favoring neuronal death. modulating neurotrophin activity. A possible scenario(s) on how Pin1 affects neu- Possible physiologic and therapeutic rotrophin activity is now described. As stated implications before, Pin1 is the only known isomerase that If inhibition or stimulation of Pin1 may cause an specifically catalyzes the phosphorylated pThr/ alteration in neurotrophins or their receptor levels pSer-Pro motifs from cis-configuration to trans- and/or their functionality, this may introduce the configuration. Induction of serine/threonine possibility of modulating these proteins epigeneti- kinase activity is critical for cell survival and pro- cally and not by exogenous administration, the liferation, and is part of the signal transduction method investigated most so far. The fact that cascade of neurotrophins. Specifically, among epigenetic mechanisms, such those regulated by the pathways activated by neurotrophins through Pin1, are reversible as opposed to genetic modifi- the Trk receptors, a survival pathway includes cation, is even more intriguing. Nonetheless, it is the activation of the serine/threonine protein clear that the loop between Pin1 and neurotro- kinase B (also known as Akt). phin needs to be in equilibrium, otherwise favor- ing one (cancer) or the other (neurodegenerative Akt plays an essential role in cell survival, growth, disorders) pathological process. migration, and proliferation, Altered Akt activity has been associated with cancer and other disease Funding conditions, including neurodegenerative diseases. The author(s) received no financial support for Recent reports have shown that the stability of the research, authorship, and/or publication of Akt protein is regulated through phosphorylation this article. on its Thr-Pro motifs and that Pin1 is a crucial factor for Akt stability and activation phospho- Conflict of interest statement rylation [Liao et  al. 2009]. By this mechanism The author(s) declared no potential conflicts of Pin1 can be a molecular ‘timer’ or ‘switch’, turn- interest with respect to the research, authorship, ing neurotrophin pathways ‘on’ or ‘off’. and/or publication of this article. http://tam.sagepub.com 61 Therapeutic Advances in Medical Oncology 9(1) signalling and disease. Nat Rev Mol Cell Biol 8: References 904–916. Brynczka, C., Labhart, P. and Merrick, B. (2007) NGF-mediated transcriptional targets of p53 in PC12 Ma, L., Yu, J., Wang, H., Meng, X., Tan, C., Wang, neuronal differentiation. BMC Genomics 8: 139. C. et al. (2014) Association between cancer and Alzheimer’s disease: systematic review and meta- Driver, J., Zhou, X. and Lu, K. (2015) Pin1 analysis. J Alzheimers Dis 42: 565–573. dysregulation helps to explain the inverse association between cancer and Alzheimer’s disease. Biochim Musicco, M., Adorni, F., Di Santo, S., Prinelli, F., Biophys Acta 1850: 2069–2076. Pettenati, C., Caltagirone, C. et al. (2013) Inverse occurrence of cancer and Alzheimer disease: a Finn, G. and Lu, K. (2008) Phosphorylation-specific population-based incidence study. Neurology 81: prolyl isomerase Pin1 as a new diagnostic and 322–328. therapeutic target for cancer. Curr Cancer Drug Targets 8: 223–229. Nakagawara, A. (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Hondermarck, H. (2012) Neurotrophins and their Cancer Lett 169: 107–114. receptors in breast cancer. Cytokine Growth Factor Rev 23: 357–365. Nakagawara, A., Arima-Nakagawara, M., Scavarda, N., Azar, C., Cantor, A. and Brodeur, G. (1993) Hu, H. and Wulf, G. (2011) The amplifier effect: how Association between high levels of expression of Pin1 empowers mutant p53. Breast Cancer Res 13: the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 328: 847–854. Huang, E. and Reichardt, L. (2001) Neurotrophins: Nicole Tsang, Y., Wu, X., Lim, J., Wee Ong, C., roles in neuronal development and function. 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Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Aug 23, 2016

Keywords: cancer; neurodegeneration; neurotrophins; p53; Pin1

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