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.

  • Original Article
  • Published:

p53-Mediated upregulation of DcR1 impairs oxaliplatin/TRAIL-induced synergistic anti-tumour potential in colon cancer cells

Abstract

Oxaliplatin has emerged as a major chemotherapeutic drug in the treatment of advanced colorectal cancer, yet like most conventional cancer therapeutics, its efficacy is often compromised due to p53 mutations. Unlike oxaliplatin, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a p53-independent manner, and chemotherapy is known to overcome tumour resistance to TRAIL-induced cell death in most cancer cells. Using a panel of colon cancer cell lines, we assessed the ability of oxaliplatin to sensitize to TRAIL-induced apoptosis. We demonstrate that while both drugs additively or synergistically induced apoptosis in almost all cell lines tested, p53 wild-type colon cancer cells such as HCT116, LS513 or LS174T remained resistant. Impaired TRAIL-induced cell death resulted from a strong p53 dependent, oxaliplatin-mediated, DcR1 receptor expression increase. According to our finding, downregulation of DcR1 using siRNA, in p53 wild-type colon cancer cells, restored oxaliplatin/TRAIL synergistic apoptotic activity. On the contrary, exogenous DcR1 overexpression in SW480, a p53-mutated cell line, abolished the synergy between the two drugs. Altogether we demonstrate for the first time that p53 negatively regulates oxaliplatin-mediated TRAIL-induced apoptotic activity through DcR1 upregulation. Our findings could have important implications for future therapeutic strategies, and suggest that the association oxaliplatin/TRAIL should be restricted to patients harbouring a non-functional p53 protein.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ashkenazi A . (2002). Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2: 420–430.

    Article  CAS  Google Scholar 

  • Bouralexis S, Findlay DM, Atkins GJ, Labrinidis A, Hay S, Evdokiou A . (2003). Progressive resistance of BTK-143 osteosarcoma cells to Apo2L/TRAIL-induced apoptosis is mediated by acquisition of DcR2/TRAIL-R4 expression: resensitisation with chemotherapy. Br J Cancer 89: 206–214.

    Article  CAS  Google Scholar 

  • Bouralexis S, Findlay DM, Evdokiou A . (2005). Death to the bad guys: targeting cancer via Apo2L/TRAIL. Apoptosis 10: 35–51.

    Article  CAS  Google Scholar 

  • Chou TC, Talalay P . (1984). Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27–55.

    Article  CAS  Google Scholar 

  • Clancy L, Mruk K, Archer K, Woelfel M, Mongkolsapaya J, Screaton G et al. (2005). Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci USA 102: 18099–18104.

    Article  CAS  Google Scholar 

  • Davidovich IA, Levenson AS, Levenson Chernokhvostov VV . (2004). Overexpression of DcR1 and survivin in genetically modified cells with pleiotropic drug resistance. Cancer Lett 211: 189–197.

    Article  CAS  Google Scholar 

  • Galligan L, Longley DB, McEwan M, Wilson TR, McLaughlin K, Johnston PG . (2005). Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP. Mol Cancer Ther 4: 2026–2036.

    Article  CAS  Google Scholar 

  • Gayet J, Zhou XP, Duval A, Rolland S, Hoang JM, Cottu P et al. (2001). Extensive characterization of genetic alterations in a series of human colorectal cancer cell lines. Oncogene 20: 5025–5032.

    Article  CAS  Google Scholar 

  • Grady WM, Markowitz SD . (2002). Genetic and epigenetic alterations in colon cancer. Annu Rev Genomics Hum Genet 3: 101–128.

    Article  CAS  Google Scholar 

  • Gramont A . (2005). Adjuvant therapy of stage II and III colon cancer. Semin Oncol 32: 11–14.

    Article  Google Scholar 

  • He Q, Huang Y, Sheikh MS . (2004). Proteasome inhibitor MG132 upregulates death receptor 5 and cooperates with Apo2L/TRAIL to induce apoptosis in Bax-proficient and -deficient cells. Oncogene 23: 2554–2558.

    Article  CAS  Google Scholar 

  • Jang SH, Seol JY, Kim CH, Yoo CG, Kim YW, Han SK et al. (2004). Additive effect of TRAIL and p53 gene transfer on apoptosis of human lung cancer cell lines. Int J Mol Med 13: 181–186.

    CAS  PubMed  Google Scholar 

  • Jin H, Yang R, Fong S, Totpal K, Lawrence D, Zheng Z et al. (2004). Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Cancer Res 64: 4900–4905.

    Article  CAS  Google Scholar 

  • Kelley SK, Ashkenazi A . (2004). Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol 4: 333–339.

    Article  CAS  Google Scholar 

  • Kim YH, Park JW, Lee JY, Kwon TK . (2004). Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells. Carcinogenesis 25: 1813–1820.

    Article  Google Scholar 

  • LeBlanc HN, Ashkenazi A . (2003). Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 10: 66–75.

    Article  CAS  Google Scholar 

  • Liu X, Yue P, Khuri FR, Sun SY . (2005). Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity. Cancer Res 65: 9169–9175.

    Article  CAS  Google Scholar 

  • Merino D, Lalaoui N, Morizot A, Schneider P, Solary E, Micheau O . (2006). Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Mol Cell Biol 26: 7046–7055.

    Article  CAS  Google Scholar 

  • Merino D, Lalaoui N, Morizot A, Solary E, Micheau O . (2007). TRAIL in cancer therapy: present and future challenges. Expert Opin Ther Targets 11: 1299–1314.

    Article  CAS  Google Scholar 

  • Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT . (1999). Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J Biol Chem 274: 7987–7992.

    Article  CAS  Google Scholar 

  • Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J . (2001). NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol 21: 5299–5305.

    Article  CAS  Google Scholar 

  • Mita MM, Ochoa L, Rowinsky EK, Kuhn J, Schwartz G, Hammond LA et al. (2006). A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer. Ann Oncol 17: 313–321.

    Article  CAS  Google Scholar 

  • Motoki K, Mori E, Matsumoto A, Thomas M, Tomura T, Humphreys R et al. (2005). Enhanced apoptosis and tumor regression induced by a direct agonist antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2. Clin Cancer Res 11: 3126–3135.

    Article  CAS  Google Scholar 

  • Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK, Huang HJ . (2000). Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 60: 847–853.

    CAS  PubMed  Google Scholar 

  • Oren M . (2003). Decision making by p53: life, death and cancer. Cell Death Differ 10: 431–442.

    Article  CAS  Google Scholar 

  • Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM . (1997). An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277: 815–818.

    Article  CAS  Google Scholar 

  • Pukac L, Kanakaraj P, Humphreys R, Alderson R, Bloom M, Sung C et al. (2005). HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Br J Cancer 92: 1430–1441.

    Article  CAS  Google Scholar 

  • Ruiz de Almodovar C, Ruiz-Ruiz C, Rodriguez A, Ortiz-Ferron G, Redondo JM, Lopez-Rivas A . (2004). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) decoy receptor TRAIL-R3 is up-regulated by p53 in breast tumor cells through a mechanism involving an intronic p53-binding site. J Biol Chem 279: 4093–4101.

    Article  CAS  Google Scholar 

  • Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH, Peter ME . (1999). Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem 274: 22532–22538.

    Article  CAS  Google Scholar 

  • Shankar S, Srivastava RK . (2004). Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist Updat 7: 139–156.

    Article  CAS  Google Scholar 

  • Sheikh MS, Fornace Jr AJ . (2000). Death and decoy receptors and p53-mediated apoptosis. Leukemia 14: 1509–1513.

    Article  CAS  Google Scholar 

  • Steel GG, Peckham MJ . (1979). Exploitable mechanisms in combined radiotherapy-chemotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 5: 85–91.

    Article  CAS  Google Scholar 

  • Thorburn A . (2004). Death receptor-induced cell killing. Cell Signal 16: 139–144.

    Article  CAS  Google Scholar 

  • Toscano F, Parmentier B, Fajoui ZE, Estornes Y, Chayvialle JA, Saurin JC et al. (2007). p53 dependent and independent sensitivity to oxaliplatin of colon cancer cells. Biochem Pharmacol 74: 392–406.

    Article  CAS  Google Scholar 

  • Van Geelen CM, Westra JL, de Vries EG, Boersma-van Ek W, Zwart N, Hollema H et al. (2006). Prognostic significance of tumor necrosis factor-related apoptosis-inducing ligand and its receptors in adjuvantly treated stage III colon cancer patients. J Clin Oncol 24: 4998–5004.

    Article  CAS  Google Scholar 

  • Vignati S, Codegoni A, Polato F, Broggini M . (2002). TRAIL activity in human ovarian cancer cells: potentiation of the action of cytotoxic drugs. Eur J Cancer 38: 177–183.

    Article  CAS  Google Scholar 

  • Wajant H, Gerspach J, Pfizenmaier K . (2005). Tumor therapeutics by design: targeting and activation of death receptors. Cytokine Growth Factor Rev 16: 55–76.

    Article  CAS  Google Scholar 

  • Yagita H, Takeda K, Hayakawa Y, Smyth MJ, Okumura K . (2004). TRAIL and its receptors as targets for cancer therapy. Cancer Sci 95: 777–783.

    Article  CAS  Google Scholar 

  • Yamanaka T, Shiraki K, Sugimoto K, Ito T, Fujikawa K, Ito M et al. (2000). Chemotherapeutic agents augment TRAIL-induced apoptosis in human hepatocellular carcinoma cell lines. Hepatology 32: 482–490.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ligue Nationale contre le Cancer (Comité du Rhône), the INCa (Institut National du Cancer) and the Cancéropôle Lyon-Auvergne-Rhône-Alpes (CLARA). F Toscano is a doctoral fellow from the Ligue Nationale contre le Cancer. N Lalaoui is supported by a doctoral joint fellowship from the INSERM and the Conseil Régional de Bourgogne. O Micheau is supported by research grants from the INCa (PL 098), ANR (Agence Nationale de la Recherche, ANR-06-JCJC-0103) and the European Community (ApopTrain Marie Curie RTN). We acknowledge the CeCIL (Centre Commun d'Imagerie Laënnec) for providing part of the technical devices (flow cytometer) used in this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J Abello.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Toscano, F., Fajoui, Z., Gay, F. et al. p53-Mediated upregulation of DcR1 impairs oxaliplatin/TRAIL-induced synergistic anti-tumour potential in colon cancer cells. Oncogene 27, 4161–4171 (2008). https://doi.org/10.1038/onc.2008.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.52

Keywords

This article is cited by

Search

Quick links