Perspective

The interplay between mutant p53 and the mevalonate pathway

  • Cell Death & Differentiationvolume 25pages460470 (2018)
  • doi:10.1038/s41418-017-0026-y
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Abstract

Missense mutations in the TP53 gene lead to accumulation of dysfunctional TP53 proteins in tumors, showing oncogenic gain-of-function (GOF) activities. Stabilization of mutant TP53 (mutp53) is required for the GOF; however, the mechanisms by which mutp53 promotes cancer progression and how mutp53 stability is regulated are not completely understood. Recent work from our laboratory has identified statins, inhibitors of the mevalonate pathway, as degraders of conformational mutp53. Specific reduction of mevalonate-5-phosphate (MVP), a metabolic intermediate in the mevalonate pathway, by statins or mevalonate kinase (MVK) knockdown triggers CHIP ubiquitin ligase-mediated degradation of conformational mutp53 by inhibiting interaction between mutp53 and DNAJA1, a Hsp40 family member. Thus, the mevalonate pathway contributes to mutp53 stabilization. Given that mutp53 is shown to promote cancer progression by upregulating mRNA expression of mevalonate pathway enzymes by binding to the sterol regulatory element-binding protein 2 (SREBP2) and subsequently increasing activities of mevalonate pathway-associated oncogenic proteins (e.g., Ras, Rho, YAP/TAZ), there is a positive-feedback loop between mutp53 and the mevalonate pathway. Here, we summarize recent evidence linking the mevalonate pathway-mutp53 axis with cancer progression and further discuss the clinical relevance of this axis.

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References

  1. 1.

    Lane D, Levine A. p53 Research: the past thirty years and the next thirty years. Cold Spring Harbor Perspect Biol 2010;2:a000893.

  2. 2.

    Levav-Cohen Y, Goldberg Z, Tan KH, Alsheich-Bartok O, Zuckerman V, Haupt S, et al. The p53-Mdm2 loop: a critical juncture of stress response. Subcell Biochem 2014;85:161–86.

  3. 3.

    Vaseva AV, Moll UM. The mitochondrial p53 pathway. Biochim Biophys Acta 2009;1787:414–20.

  4. 4.

    Parrales A, Iwakuma T. Targeting oncogenic mutant p53 for cancer therapy. Front Oncol 2015;5:288.

  5. 5.

    Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol 2013;15:2–8.

  6. 6.

    Berkers CR, Maddocks OD, Cheung EC, Mor I, Vousden KH. Metabolic regulation by p53 family members. Cell Metab 2013;18:617–33.

  7. 7.

    Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes Cancer 2011;2:466–74.

  8. 8.

    Goh AM, Coffill CR, Lane DP. The role of mutant p53 in human cancer. J Pathol 2011;223:116–26.

  9. 9.

    Costa DC, de Oliveira GA, Cino EA, Soares IN, Rangel LP, Silva JL. Aggregation and prion-like properties of misfolded tumor suppressors: is cancer a prion disease? Cold Spring Harbor Perspect Biol 2016;8:10.

  10. 10.

    Silva JL, De Moura Gallo CV, Costa DC, Rangel LP. Prion-like aggregation of mutant p53 in cancer. Trends Biochem Sci 2014;39:260–67.

  11. 11.

    Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A, et al. Gain of function of mutantp53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell 2006;10:191–202.

  12. 12.

    Ferraiuolo M, Di Agostino S, Blandino G, Strano S. Oncogenic Intra-p53 Family Member Interactions in Human Cancers. Front Oncol 2016;6:77.

  13. 13.

    Do PM, Varanasi L, Fan S, Li C, Kubacka I, Newman V, et al. Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes Dev 2012;26:830–45.

  14. 14.

    Zhou G, Wang J, Zhao M, Xie TX, Tanaka N, Sano D, et al. Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol Cell 2014;54:960–74.

  15. 15.

    Xu J, Reumers J, Couceiro JR, De Smet F, Gallardo R, Rudyak S, et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat Chem Biol 2011;7:285–95.

  16. 16.

    Adhikari AS, Iwakuma T. Mutant p53 gain of oncogenic function: in vivo evidence, mechanism of action and its clinical implications. Fukuoka Igaku Zasshi 2009;100:217–28.

  17. 17.

    Freed-Pastor WA, Prives C. Mutantp53: one name, many proteins. Genes Dev 2012;26:1268–86.

  18. 18.

    Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA, et al. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 2008;22:1337–44.

  19. 19.

    Iwakuma T, Lozano G, Flores ER. Li-Fraumeni syndrome: a p53 family affair. Cell Cycle (Georgetown, Tex) 2005;4:865–7.

  20. 20.

    Alexandrova EM, Yallowitz AR, Li D, Xu S, Schulz R, Proia DA, et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 2015;523:352–6.

  21. 21.

    Iyer SV, Parrales A, Begani P, Narkar A, Adhikari AS, Martinez LA, et al. Allele-specific silencing of mutant p53 attenuates dominant-negative and gain-of-function activities. Oncotarget 2016;7:5401–15.

  22. 22.

    Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G, Sacchi A. Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 2006;25:304–9.

  23. 23.

    Parrales, A, Ranjan A, Iyer SV, Padhye S, Weir SJ, Roy A, et al. DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. Nat Cell Biol 2016;18:1233-43.

  24. 24.

    Davies JT, Delfino SF, Feinberg CE, Johnson MF, Nappi VL, Olinger JT, et al. Current and emerging uses of statins in clinical therapeutics: a review. Lipid Insights 2016;9:13–29.

  25. 25.

    Aviles A, Neri N, Huerta-Guzman J, Nambo MJ. Randomized clinical trial of zoledronic acid in multiple myeloma patients undergoing high-dose chemotherapy and stem-cell transplantation. Curr Oncol 2013;20:e13–20.

  26. 26.

    Coleman RE, Seaman JJ. The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases. Semin Oncol 2001;28(2Suppl 6):11–16.

  27. 27.

    Appels NM, Beijnen JH, Schellens JH. Development of farnesyl transferase inhibitors: a review. Oncologist 2005;10:565–78.

  28. 28.

    Lobell RB, Liu D, Buser CA, Davide JP, DePuy E, Hamilton K, et al. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl: protein transferase type-I. Mol Cancer Ther 2002;1:747–58.

  29. 29.

    Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 2012;148:244–58.

  30. 30.

    Thurnher M, Gruenbacher G, Nussbaumer O. Regulation of mevalonate metabolism in cancer and immune cells. Biochim Biophys Acta 2013;1831:1009–1015.

  31. 31.

    Thurnher M, Nussbaumer O, Gruenbacher G. Novel aspects of mevalonate pathway inhibitors as antitumor agents. Clinical Cancer Res 2012;18:3524–31.

  32. 32.

    Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 2007;40:575–84.

  33. 33.

    Gobel A, Thiele S, Browne AJ, Rauner M, Zinna VM, Hofbauer LC, et al. Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells. Cancer Lett 2016;375:162–71.

  34. 34.

    Duncan RE, El-Sohemy A, Archer MC. Mevalonate promotes the growth of tumors derived from human cancer cells in vivo and stimulates proliferation in vitro with enhanced cyclin-dependent kinase-2 activity. J Biol Chem 2004;279:33079–84.

  35. 35.

    Clendening JW, Pandyra A, Boutros PC, El Ghamrasni S, Khosravi F, Trentin GA, et al. Dysregulation of the mevalonate pathway promotes transformation. Proc Natl Acad Sci USA 2010;107:15051–56.

  36. 36.

    Vallianou NG, Kostantinou A, Kougias M, Kazazis C. Statins and cancer. Anticancer Agents Med Chem 2014;14:706–12.

  37. 37.

    Fourie AM, Hupp TR, Lane DP, Sang BC, Barbosa MS, Sambrook JF, et al. HSP70 binding sites in the tumor suppressor protein p53. J Biol Chem 1997;272:19471–79.

  38. 38.

    Edkins AL. CHIP: a co-chaperone for degradation by the proteasome. Subcell Biochem 2015;78:219–42.

  39. 39.

    Li D, Marchenko ND, Moll UM. SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ 2011;18:1904–13.

  40. 40.

    Wang C, Chen J. Phosphorylation and hsp90 binding mediate heat shock stabilization of p53. J Biol Chem 2003;278:2066–71.

  41. 41.

    Peng Y, Chen L, Li C, Lu W, Chen J. Inhibition of MDM2 by hsp90 contributes to mutant p53 stabilization. J Biol Chem 2001;276:40583–90.

  42. 42.

    Xu W, Marcu M, Yuan X, Mimnaugh E, Patterson C, Neckers L. Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci U S A 2002;99:12847–52.

  43. 43.

    King FW, Wawrzynow A, Hohfeld J, Zylicz M. Co-chaperones Bag-1, Hop and Hsp40 regulate Hsc70 and Hsp90 interactions with wild-type or mutant p53. EMBO J 2001;20:6297–6305.

  44. 44.

    Kampinga HH, Kanon B, Salomons FA, Kabakov AE, Patterson C. Overexpression of the cochaperone CHIP enhances Hsp70-dependent folding activity in mammalian cells. Mol Cell Biol 2003;23:4948–58.

  45. 45.

    Lin YC, Lin JH, Chou CW, Chang YF, Yeh SH, Chen CC. Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1/2. Cancer Res 2008;68:2375–83.

  46. 46.

    Karlic H, Thaler R, Gerner C, Grunt T, Proestling K, Haider F, et al. Inhibition of the mevalonate pathway affects epigenetic regulation in cancer cells. Cancer Genet 2015;208:241–252.

  47. 47.

    Warita K, Warita T, Beckwitt CH, Schurdak ME, Vazquez A, Wells A, et al. Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion. Sci Rep 2014;4:7593.

  48. 48.

    Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer 2016;16:718–31.

  49. 49.

    Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell 2006;124:35–46.

  50. 50.

    Likus W, Siemianowicz K, Bienk K, Pakula M, Pathak H, Dutta C, et al. Could drugs inhibiting the mevalonate pathway also target cancer stem cells? Drug Resistance Updates 2016;25:13–25.

  51. 51.

    Elsayed M, Kobayashi D, Kubota T, Matsunaga N, Murata R, Yoshizawa Y, et al. Synergistic antiproliferative effects of zoledronic acid and fluvastatin on human pancreatic cancer cell lines: an in vitro study. Biol Pharm Bull 2016;39:1238–46.

  52. 52.

    Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al.et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104–10.

  53. 53.

    Buganim Y, Solomon H, Rais Y, Kistner D, Nachmany I, Brait M, et al. p53 Regulates the Ras circuit to inhibit the expression of a cancer-related gene signature by various molecular pathways. Cancer Res 2010;70:2274–84.

  54. 54.

    Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 2002;12:9–18.

  55. 55.

    Wang W, Cheng B, Miao L, Mei Y, Wu M. Mutant p53-R273H gains new function in sustained activation of EGFR signaling via suppressing miR-27a expression. Cell Death Dis 2013;4:e574.

  56. 56.

    Bustelo XR, Sauzeau V, Berenjeno IM. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 2007;29:356–70.

  57. 57.

    Ginestier C, Monville F, Wicinski J, Cabaud O, Cervera N, Josselin E, et al. Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target. Stem Cells 2012;30:1327–37.

  58. 58.

    Mizuarai S, Yamanaka K, Kotani H. Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells. Cancer Res 2006;66:6319–26.

  59. 59.

    Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 2015;15:73–9.

  60. 60.

    Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, et al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol 2014;16:357–66.

  61. 61.

    Wang Z, Wu Y, Wang H, Zhang Y, Mei L, Fang X, et al. Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci USA 2014;111:E89–98.

  62. 62.

    Mo JS, Yu FX, Gong R, Brown JH, Guan KL. Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev 2012;26:2138–43.

  63. 63.

    Di Agostino S, Sorrentino G, Ingallina E, Valenti F, Ferraiuolo M, Bicciato S, et al. YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins. EMBO Rep 2016;17:188–201.

  64. 64.

    Escoll M, Gargini R, Cuadrado A, Anton IM, Wandosell F. Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ. Oncogene 2017;36:3515–27.

  65. 65.

    Alfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nat Rev Urol 2017;14:107–119.

  66. 66.

    Feng CH, Miller CM, Tenney ME, Lee NK, Yamada SD, Hasan Y. Statin use significantly improves overall survival in high-grade endometrial cancer. Int J Gynecol Cancer 2016;26:1642–49.

  67. 67.

    Gray RT, Coleman HG, Hughes C, Murray LJ, Cardwell CR. Statin use and survival in colorectal cancer: results from a population-based cohort study and an updated systematic review and meta-analysis. Cancer Epidemiol 2016;45:71–81.

  68. 68.

    Nayan M, Punjani N, Juurlink DN, Finelli A, Austin PC, Kulkarni GS, et al. Statin use and kidney cancer survival outcomes: A systematic review and meta-analysis. Cancer Treat Rev 2017;52:105–116.

  69. 69.

    Sanfilippo, KM, Keller J, Gage BF, Luo S, Wang TF, Moskowitz G, et al. Statins are associated with reduced mortality in multiple myeloma. J Clin Oncol 2016;34:4008-14.

  70. 70.

    Mei Z, Liang M, Li L, Zhang Y, Wang Q, Yang W. Effects of statins on cancer mortality and progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals. Int J Cancer 2017;140:1068–81.

  71. 71.

    Kautzky-Willer A, Thurner S, Klimek P. Use of statins offsets insulin-related cancer risk. J Intern Med 2017;281:206–16.

  72. 72.

    Undela K, Srikanth V, Bansal D. Statin use and risk of breast cancer: a meta-analysis of observational studies. Breast Cancer Res Treat 2012;135:261–9.

  73. 73.

    Nordstrom T, Clements M, Karlsson R, Adolfsson J, Gronberg H. The risk of prostate cancer for men on aspirin, statin or antidiabetic medications. Eur J Cancer 2015;51:725–33.

  74. 74.

    Alliance for Clinical Trials in Oncology. URL: https://clinicaltrials.gov/ct2/results?cond=&term=zoledronic+acid&cntry1=&state1=&recrs=

  75. 75.

    Dudakovic A, Tong H, Hohl RJ. Geranylgeranyl diphosphate depletion inhibits breast cancer cell migration. Invest New Drugs 2011;29:912–20.

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Acknowledgements

We thank Atul Ranjan and Satomi Yamamoto for editing the manuscript and helpful discussion. This manuscript is supported by NIH R01 CA174735 (T.I.) grant.

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Author notes

  1. Edited by G. Melino

Affiliations

  1. Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA

    • Alejandro Parrales
    • , Elizabeth Thoenen
    •  & Tomoo Iwakuma

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Conflict of interest

The authors declare that they have no competing interests.

Corresponding author

Correspondence to Tomoo Iwakuma.