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CP-31398 inhibits the growth of p53-mutated liver cancer cells in vitro and in vivo

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Tumor Biology

Abstract

The tumor suppressor p53 is one of the most frequently mutated genes in hepatocellular carcinoma (HCC). Previous studies demonstrated that CP-31398 restored the native conformation of mutant p53 and trans-activated p53 downstream genes in tumor cells. However, the research on the application of CP-31398 to liver cancer has not been reported. Here, we investigated the effects of CP-31398 on the phenotype of HCC cells carrying p53 mutation. The effects of CP-31398 on the characteristic of p53-mutated HCC cells were evaluated through analyzing cell cycle, cell apoptosis, cell proliferation, and the expression of p53 downstream genes. In tumor xenografts developed by PLC/PRF/5 cells, the inhibition of tumor growth by CP-31398 was analyzed through gross morphology, growth curve, and the expression of p53-related genes. Firstly, we demonstrated that CP-31398 inhibited the growth of p53-mutated liver cancer cells in a dose-dependent and p53-dependent manner. Then, further study showed that CP-31398 re-activated wild-type p53 function in p53-mutated HCC cells, which resulted in inhibitive response of cell proliferation and an induction of cell-cycle arrest and apoptosis. Finally, in vivo data confirmed that CP-31398 blocked the growth of xenografts tumors through transactivation of p53-responsive downstream molecules. Our results demonstrated that CP-31398 induced desired phenotypic change of p53-mutated HCC cells in vitro and in vivo, which revealed that CP-31398 would be developed as a therapeutic candidate for HCC carrying p53 mutation.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. de Lope CR, Tremosini S, Forner A, Reig M, Bruix J. Management of hcc. J Hepatol. 2012;56 Suppl 1:S75–87.

    Article  PubMed  Google Scholar 

  3. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Oren M, Rotter V. Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol. 2010;2:a001107.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Muller PA, Vousden KH. P53 mutations in cancer. Nat Cell Biol. 2013;15:2–8.

    Article  CAS  PubMed  Google Scholar 

  7. Rippin TM, Bykov VJ, Freund SM, Selivanova G, Wiman KG, Fersht AR. Characterization of the p53-rescue drug cp-31398 in vitro and in living cells. Oncogene. 2002;21:2119–29.

    Article  CAS  PubMed  Google Scholar 

  8. He X, Liu F, Yan J, Zhang Y, Shang H, Dou Q. Trans-splicing repair of mutant p53 suppresses the growth of hepatocellular carcinoma cells in vitro and in vivo. Sci Rep. 2015;5:8705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. He X, Liao J, Liu F, Yan J, Shang H, Dou Q, et al. Functional repair of p53 mutation in colorectal cancer cells using trans-splicing. Oncotarget. 2015;6:2034–45.

    Article  PubMed  Google Scholar 

  10. Sell S. Mouse models to study the interaction of risk factors for human liver cancer. Cancer Res. 2003;63:7553–62.

    CAS  PubMed  Google Scholar 

  11. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047–63.

    Article  CAS  PubMed  Google Scholar 

  12. Liu J, Ma Q, Zhang M, Wang X, Zhang D, Li W, et al. Alterations of tp53 are associated with a poor outcome for patients with hepatocellular carcinoma: evidence from a systematic review and meta-analysis. Eur J Cancer. 2012;48:2328–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bossi G, Sacchi A. Restoration of wild-type p53 function in human cancer: relevance for tumor therapy. Head Neck. 2007;29:272–84.

    Article  PubMed  Google Scholar 

  14. Lane DP, Cheok CF, Lain S. P53-based cancer therapy. Cold Spring Harb Perspect Biol. 2010;2:a001222.

    PubMed  PubMed Central  Google Scholar 

  15. North S, El-Ghissassi F, Pluquet O, Verhaegh G, Hainaut P. The cytoprotective aminothiol wr1065 activates p21waf-1 and down regulates cell cycle progression through a p53-dependent pathway. Oncogene. 2000;19:1206–14.

    Article  CAS  PubMed  Google Scholar 

  16. Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 2002;8:282–8.

    Article  CAS  PubMed  Google Scholar 

  17. Peng Y, Li C, Chen L, Sebti S, Chen J. Rescue of mutant p53 transcription function by ellipticine. Oncogene. 2003;22:4478–87.

    Article  CAS  PubMed  Google Scholar 

  18. Demma MJ, Wong S, Maxwell E, Dasmahapatra B. Cp-31398 restores DNA-binding activity to mutant p53 in vitro but does not affect p53 homologs p63 and p73. J Biol Chem. 2004;279:45887–96.

    Article  CAS  PubMed  Google Scholar 

  19. Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, et al. Small molecule rita binds to p53, blocks p53-hdm-2 interaction and activates p53 function in tumors. Nat Med. 2004;10:1321–8.

    Article  CAS  PubMed  Google Scholar 

  20. Zache N, Lambert JM, Rokaeus N, Shen J, Hainaut P, Bergman J, et al. Mutant p53 targeting by the low molecular weight compound stima-1. Mol Oncol. 2008;2:70–80.

    Article  PubMed  Google Scholar 

  21. Yu X, Vazquez A, Levine AJ, Carpizo DR. Allele-specific p53 mutant reactivation. Cancer Cell. 2012;21:614–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fiorini C, Menegazzi M, Padroni C, Dando I, Dalla Pozza E, Gregorelli A, et al. Autophagy induced by p53-reactivating molecules protects pancreatic cancer cells from apoptosis. Apoptosis Int J Prog Cell Death. 2013;18:337–46.

    Article  CAS  Google Scholar 

  23. Rao CV, Patlolla JM, Qian L, Zhang Y, Brewer M, Mohammed A, et al. Chemopreventive effects of the p53-modulating agents cp-31398 and prima-1 in tobacco carcinogen-induced lung tumorigenesis in a/j mice. Neoplasia. 2013;15:1018–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takimoto R, Wang W, Dicker DT, Rastinejad F, Lyssikatos J, el-Deiry WS. The mutant p53-conformation modifying drug, cp-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein. Cancer Biol Ther. 2002;1:47–55.

    Article  CAS  PubMed  Google Scholar 

  25. Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, et al. Cp-31398 restores mutant p53 tumor suppressor function and inhibits uvb-induced skin carcinogenesis in mice. J Clin Invest. 2007;117:3753–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu J, Timares L, Heilpern C, Weng Z, Li C, Xu H, et al. Targeting wild-type and mutant p53 with small molecule cp-31398 blocks the growth of rhabdomyosarcoma by inducing reactive oxygen species-dependent apoptosis. Cancer Res. 2010;70:6566–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, et al. Microrna-375 targets aeg-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene. 2012;31:3357–69.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Z, Liu F, Tu W, Chang Y, Yao J, Wu W, et al. Embryonic liver fodrin involved in hepatic stellate cell activation and formation of regenerative nodule in liver cirrhosis. J Cell Mol Med. 2012;16:118–28.

    Article  CAS  PubMed  Google Scholar 

  29. Wang Z, Song Y, Tu W, He X, Lin J, Liu F. Beta-2 spectrin is involved in hepatocyte proliferation through the interaction of tgfbeta/smad and pi3k/akt signalling. Liver Int Off J Int Assoc Stud Liver. 2012;32:1103–11.

    Article  CAS  Google Scholar 

  30. He X, Kong X, Yan J, Zhang Y, Wu Q, Chang Y, et al. Cp-31398 prevents the growth of p53-mutated colorectal cancer cells in vitro and in vivo. Tumour Biol J Int Soc Oncodev Biol Med. 2015;36:1437–44.

    Article  CAS  Google Scholar 

  31. Lehmann BD, Pietenpol JA. Targeting mutant p53 in human tumors. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:3648–50.

    Article  CAS  Google Scholar 

  32. Guo J, Xin H. Chinese gene therapy. Splicing out the west? Science. 2006;314:1232–5.

    Article  CAS  PubMed  Google Scholar 

  33. Levesque AA, Eastman A. P53-based cancer therapies: is defective p53 the achilles heel of the tumor? Carcinogenesis. 2007;28:13–20.

    Article  CAS  PubMed  Google Scholar 

  34. Foster BA, Coffey HA, Morin MJ, Rastinejad F. Pharmacological rescue of mutant p53 conformation and function. Science. 1999;286:2507–10.

    Article  CAS  PubMed  Google Scholar 

  35. Wang W, Takimoto R, Rastinejad F, El-Deiry WS. Stabilization of p53 by cp-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or mdm2 binding. Mol Cell Biol. 2003;23:2171–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Roh JL, Kang SK, Minn I, Califano JA, Sidransky D, Koch WM. P53-reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma. Oral Oncol. 2011;47:8–15.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No.81072003, 81270506, 81472832) and the Outstanding Youth Science Foundation of Tongji Hospital (No. YXQN005).

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Authors and Affiliations

  1. Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Xing-Xing He, Yu-Nan Zhang, Jun-Wei Yan, Jing-Jun Yan & Qian Wu

  2. Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China

    Xing-Xing He & Yu-Hu Song

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  1. Xing-Xing He
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  2. Yu-Nan Zhang
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Correspondence to Yu-Hu Song.

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He, XX., Zhang, YN., Yan, JW. et al. CP-31398 inhibits the growth of p53-mutated liver cancer cells in vitro and in vivo. Tumor Biol. 37, 807–815 (2016). https://doi.org/10.1007/s13277-015-3857-5

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  • DOI: https://doi.org/10.1007/s13277-015-3857-5

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