Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed

Abstract

The majority of malignant mesothelioma possesses the wild-type p53 gene with a homologous deletion of the INK4A/ARF locus containing the p14ARF and the p16INK4A genes. We examined whether forced expression of p53 inhibited growth of mesothelioma cells and produced anti-tumor effects by a combination of cisplatin (CDDP) or pemetrexed (PEM), the first-line drugs for mesothelioma treatments. Transduction of mesothelioma cells with adenoviruses bearing the p53 gene (Ad-p53) induced phosphorylation of p53, upregulated Mdm2 and p21 expression levels and decreased phosphorylation of pRb. The transduction generated cleavage of caspase-8 and -3, but not caspase-9. Cell cycle analysis showed increased G0/G1- or G2/M-phase populations and subsequently sub-G1 fractions, depending on cell types and Ad-p53 doses. Transduction with Ad-p53 suppressed viability of mesothelioma cells and augmented the growth inhibition by CDDP or PEM mostly in a synergistic manner. Intrapleural injection of Ad-p53 and systemic administration of CDDP produced anti-tumor effects in an orthotopic animal model. These data collectively suggest that Ad-p53 is a possible agent for mesothelioma in combination with the first-line chemotherapeutics.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Carbone M, Kratzke RA, Testa JR . The pathogenesis of mesothelioma. Semin Oncol 2002; 29: 2–17.

    CAS  Article  Google Scholar 

  2. Robinson BW, Musk AW, Lake RA . Malignant mesothelioma. Lancet 2005; 366: 397–408.

    CAS  Article  Google Scholar 

  3. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636–2644.

    CAS  Article  Google Scholar 

  4. Lee AY, Raz DJ, He B, Jablons DM . Update on the molecular biology of malignant mesothelioma. Cancer 2007; 109: 1454–1461.

    CAS  Article  Google Scholar 

  5. Frizelle SP, Grim J, Zhou J, Gupta P, Curiel DT, Geradts J et al. Re-expression of p16INK4a in mesothelioma cells results in cell cycle arrest, cell death, tumor suppression and tumor regression. Oncogene 1998; 16: 3087–3095.

    CAS  Article  Google Scholar 

  6. Yang CT, You L, Yeh CC, Chang JW, Zhang F, McCormick F et al. Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells. J Natl Cancer Inst 2000; 92: 636–641.

    CAS  Article  Google Scholar 

  7. Frizelle SP, Rubins JB, Zhou JX, Curiel DT, Kratzke RA . Gene therapy of established mesothelioma xenografts with recombinant p16INK4a adenovirus. Cancer Gene Ther 2000; 7: 1421–1425.

    CAS  Article  Google Scholar 

  8. Yang CT, You L, Uematsu K, Yeh CC, McCormick F, Jablons DM . p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53. Cancer Res 2001; 61: 5959–5963.

    CAS  Google Scholar 

  9. Hopkins-Donaldson S, Belyanskaya LL, Simoes-Wust AP, Sigrist B, Kurtz S, Zangemeister-Wittke U et al. p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma. Neoplasia 2006; 8: 551–559.

    CAS  Article  Google Scholar 

  10. St John LS, Sauter ER, Herlyn M, Litwin S, Adler-Storthz K . Endogenous p53 gene status predicts the response of human squamous cell carcinomas to wild-type p53. Cancer Gene Ther 2000; 7: 749–756.

    CAS  Article  Google Scholar 

  11. Giuliano M, Catalano A, Strizzi L, Vianale G, Capogrossi M, Procopio A . Adenovirus-mediated wild-type p53 overexpression reverts tumourigenicity of human mesothelioma cells. Int J Mol Med 2000; 5: 591–596.

    CAS  PubMed  Google Scholar 

  12. Pochampally R, Fodera B, Chen L, Shao W, Levine EA, Chen J . A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells. Oncogene 1998; 17: 2629–2636.

    CAS  Article  Google Scholar 

  13. Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser46-phosphorylated p53. Cell 2000; 102: 849–862.

    CAS  Article  Google Scholar 

  14. Zhao H, Traganos F, Darzynkiewicz Z . Phosphorylation of p53 on Ser15 during cell cycle caused by Topo I and Topo II inhibitors in relation to ATM and Chk2 activation. Cell Cycle 2008; 7: 3048–3055.

    CAS  Article  Google Scholar 

  15. Ungar S, Van de Meeren A, Tammilehto L, Linnainmaa K, Mattson K, Gerwin BI . High levels of MDM2 are not correlated with the presence of wild-type p53 in human malignant mesothelioma cell lines. Br J Cancer 1996; 74: 1534–1540.

    CAS  Article  Google Scholar 

  16. Kuribayashi K, Krigsfeld G, Wang W, Xu J, Mayes PA, Dicker DT et al. TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell death. Cancer Biol Ther 2008; 7: 2034–2048.

    CAS  Article  Google Scholar 

  17. Shinoura N, Sakurai S, Shibasaki F, Asai A, Kirino T, Hamada H . Co-transduction of Apaf-1 and caspase-9 highly enhances p53-mediated apoptosis in gliomas. Br J Cancer 2002; 86: 587–595.

    CAS  Article  Google Scholar 

  18. Yang C, You L, Lin Y, Lin C, McCormick F, Jablons DM . A comparison analysis of anti-tumor efficacy of adenoviral gene replacement therapy (p14ARF and p16INK4A) in human mesothelioma cells. Anticancer Res 2003; 23: 33–38.

    PubMed  Google Scholar 

  19. Nguyen DM, Spitz FR, Yen N, Cristiano RJ, Roth JA . Gene therapy for lung cancer: enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer. J Thorac Cardiovasc Surg 1996; 112: 1372–1376.

    CAS  Article  Google Scholar 

  20. Quist SR, Wang-Gohrke S, Köhler T, Kreienberg R, Runnebaum IB . Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status. Cancer Gene Ther 2004; 11: 547–554.

    CAS  Article  Google Scholar 

  21. Eisold S, Linnebacher M, Ryschich E, Antolovic D, Hinz U, Klar E et al. The effect of adenovirus expressing wild-type p53 on 5-fluorouracil chemosensitivity is related to p53 status in pancreatic cancer cell lines. World J Gastroenterol 2004; 10: 3583–3589.

    CAS  Article  Google Scholar 

  22. Lu X, Errington J, Curtin NJ, Lunec J, Newell DR . The impact of p53 status on cellular sensitivity to antifolate drugs. Clin Cancer Res 2001; 7: 2114–2123.

    CAS  PubMed  Google Scholar 

  23. Giovannetti E, Backus HH, Wouters D, Ferreira CG, van Houten VM, Brakenhoff RH et al. Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels. Br J Cancer 2007; 96: 769–775.

    CAS  Article  Google Scholar 

  24. Sterman DH, Recio A, Vachani A, Sun J, Cheung L, DeLong P et al. Long-term follow-up of patients with malignant pleural mesothelioma receiving high-dose adenovirus herpes simplex thymidine kinase/ganciclovir suicide gene therapy. Clin Cancer Res 2005; 11: 7444–7453.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan and a Grant-in-aid from the Nichias Corporation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Tagawa.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Cancer Gene Therapy website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, Q., Kawamura, K., Yamanaka, M. et al. Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed. Cancer Gene Ther 19, 218–228 (2012). https://doi.org/10.1038/cgt.2011.86

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2011.86

Keywords

  • malignant mesothelioma
  • adenovirus
  • p53
  • chemotherapy

Further reading

Search

Quick links