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:

DcR2 (TRAIL-R4) siRNA and adenovirus delivery of TRAIL (Ad5hTRAIL) break down in vitro tumorigenic potential of prostate carcinoma cells

Abstract

High levels of decoy receptor 2 (DcR2; TRAIL-R4) expression are correlated with TRAIL resistance in prostate cancer cells. In addition, upregulation of TRAIL death receptor (DR4 and DR5) expression, either by ionizing radiation or chemotherapy, can sensitize cancer cells to TRAIL. Considering more than half of human cancers are TRAIL resistant, modulation of surface TRAIL receptor expression appears to be an attractive treatment modality to counteract TRAIL resistance. In this study, three siRNA duplexes targeting DcR2 receptor were tested. Ad5hTRAIL infections were performed to overexpress human full-length TRAIL to induce cell death, and the in vitro tumorigenic potential of prostate cancer cells was assessed using colony-forming assays on soft agar. The DU145 and LNCaP prostate cancer cell lines, which express high levels of DcR2, were resistant to Ad5hTRAIL-induced death. Downregulation of surface DcR2 expression by siRNA sensitized these prostate cancer cell lines to Ad5hTRAIL. In addition, DcR2 siRNA-mediated knockdown of DcR2, followed by Ad5hTRAIL infection, dramatically reduced the in vitro tumorigenic potential of prostate cancer cells. Collectively, our results suggest the potential for combining receptor-specific siRNA with TRAIL in the treatment of certain cancers.

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
Figure 8

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Griffith TS, Lynch DH . TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol 1998; 10: 559–563.

    Article  CAS  PubMed  Google Scholar 

  2. Griffith TS, Rauch CT, Smolak PJ, Waugh JY, Boiani N, Lynch DH et al. Functional analysis of TRAIL receptors using monoclonal antibodies. J Immunol 1999; 162: 2597–2605.

    CAS  PubMed  Google Scholar 

  3. Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ . Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 1998; 161: 2833–2840.

    CAS  PubMed  Google Scholar 

  4. Griffith TS, Fialkov JM, Scott DL, Azuhata T, Williams RD, Wall NR et al. Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma. Cancer Res 2002; 62: 3093–3099.

    CAS  PubMed  Google Scholar 

  5. Held J, Schulze-Osthoff K . Potential and caveats of TRAIL in cancer therapy. Drug Resist Updat 2001; 4: 243–252.

    Article  CAS  PubMed  Google Scholar 

  6. Sanlioglu AD, Koksal T, Baykara M, Luleci G, Karacay B, Sanlioglu S . Current progress in adenovirus mediated gene therapy for patients with prostate carcinoma. Gene Ther Mol Biol 2003; 7: 113–133.

    Google Scholar 

  7. Kondo K, Yamasaki S, Sugie T, Teratani N, Kan T, Imamura M et al. Cisplatin-dependent upregulation of death receptors 4 and 5 augments induction of apoptosis by TNF-related apoptosis-inducing ligand against esophageal squamous cell carcinoma. Int J Cancer 2006; 118: 230–242.

    Article  CAS  PubMed  Google Scholar 

  8. Perego P, Ciusani E, Gatti L, Carenini N, Corna E, Zunino F . Sensitization to gimatecan-induced apoptosis by tumor necrosis factor-related apoptosis inducing ligand in prostate carcinoma cells. Biochem Pharmacol 2006; 71: 791–798.

    Article  CAS  PubMed  Google Scholar 

  9. Martin S, Phillips DC, Szekely-Szucs K, Elghazi L, Desmots F, Houghton JA . Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae. Cancer Res 2005; 65: 11447–11458.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Shankar S, Singh TR, Chen X, Thakkar H, Firnin J, Srivastava RK . The sequential treatment with ionizing radiation followed by TRAIL/Apo-2L reduces tumor growth and induces apoptosis of breast tumor xenografts in nude mice. Int J Oncol 2004; 24: 1133–1140.

    CAS  PubMed  Google Scholar 

  12. Shankar S, Singh TR, Srivastava RK . Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: intracellular mechanisms. Prostate 2004; 61: 35–49.

    Article  CAS  PubMed  Google Scholar 

  13. Karacay B, Sanlioglu S, Griffith TS, Sandler A, Bonthius DJ . Inhibition of the NF-kappaB pathway enhances TRAIL-mediated apoptosis in neuroblastoma cells. Cancer Gene Ther 2004; 11: 681–690.

    Article  CAS  PubMed  Google Scholar 

  14. Wang X, Ju W, Renouard J, Aden J, Belinsky SA, Lin Y . 17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear factor-kappaB pathway. Cancer Res 2006; 66: 1089–1095.

    Article  CAS  PubMed  Google Scholar 

  15. Sanlioglu AD, Koksal IT, Karacay B, Baykara M, Luleci G, Sanlioglu S . Adenovirus-mediated IKKbetaKA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. Cancer Gene Ther 2006; 13: 21–31.

    Article  CAS  PubMed  Google Scholar 

  16. Deeb DD, Jiang H, Gao X, Divine G, Dulchavsky SA, Gautam SC . Chemosensitization of hormone-refractory prostate cancer cells by curcumin to TRAIL-induced apoptosis. J Exp Ther Oncol 2005; 5: 81–91.

    CAS  PubMed  Google Scholar 

  17. Schultze K, Bock B, Eckert A, Oevermann L, Ramacher D, Wiestler O et al. Troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via down-regulation of FLIP and Survivin. Apoptosis 2006; 11: 1503–1512.

    Article  CAS  PubMed  Google Scholar 

  18. Li X, Raikwar SP, Liu YH, Lee SJ, Zhang YP, Zhang S et al. Combination therapy of androgen-independent prostate cancer using a prostate restricted replicative adenovirus and a replication-defective adenovirus encoding human endostatin-angiostatin fusion gene. Mol Cancer Ther 2006; 5: 676–684.

    Article  CAS  PubMed  Google Scholar 

  19. Hu H, Jiang C, Schuster T, Li GX, Daniel PT, Lu J . Inorganic selenium sensitizes prostate cancer cells to TRAIL-induced apoptosis through superoxide/p53/Bax-mediated activation of mitochondrial pathway. Mol Cancer Ther 2006; 5: 1873–1882.

    Article  CAS  PubMed  Google Scholar 

  20. Fulda S, Debatin KM . 5-Aza-2′-deoxycytidine and IFN-gamma cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8. Oncogene 2006; 25: 5125–5133.

    Article  CAS  PubMed  Google Scholar 

  21. Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL . Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis. J Immunol 2000; 165: 2886–2894.

    Article  CAS  PubMed  Google Scholar 

  22. Sanlioglu S, Engelhardt JF . Cellular redox state alters recombinant adeno-associated virus transduction through tyrosine phosphatase pathways. Gene Therapy 1999; 6: 1427–1437.

    Article  CAS  PubMed  Google Scholar 

  23. Sanlioglu AD, Karacay B, Benson PK, Engelhardt JF, Sanlioglu S . Novel approaches to augment adeno-associated virus type-2 endocytosis and transduction. Virus Res 2004; 104: 51–59.

    Article  CAS  PubMed  Google Scholar 

  24. Engelhardt JF, Yang Y, Stratford-Perricaudet LD, Allen ED, Kozarsky K, Perricaudet M et al. Direct gene transfer of human CFTR into human bronchial epithelia of xenografts with E1-deleted adenoviruses. Nat Genet 1993; 4: 27–34.

    Article  CAS  PubMed  Google Scholar 

  25. Doerschug K, Sanlioglu S, Flaherty DM, Wilson RL, Yarovinsky T, Monick MM et al. First-generation adenovirus vectors shorten survival time in a murine model of sepsis. J Immunol 2002; 169: 6539–6545.

    Article  CAS  PubMed  Google Scholar 

  26. Sanlioglu AD, Dirice E, Aydin C, Erin N, Koksoy S, Sanlioglu S . Surface TRAIL decoy receptor-4 expression is correlated with TRAIL resistance in MCF7 breast cancer cells. BMC Cancer 2005; 5: 54.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Aydin C, Sanlioglu AD, Karacay B, Ozbilim G, Dertsiz L, Ozbudak O et al. Decoy receptor-2 small interfering RNA (siRNA) strategy employing three different siRNA constructs in combination defeats adenovirus-transferred tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells. Hum Gene Ther 2007; 18: 39–50.

    Article  CAS  PubMed  Google Scholar 

  28. Sanlioglu AD, Koksal IT, Ciftcioglu A, Baykara M, Luleci G, Sanlioglu S . Differential expression of TRAIL and its receptors in benign and malignant prostate tissues. J Urol 2007; 177: 359–364.

    Article  PubMed  Google Scholar 

  29. Malhi H, Gores GJ . TRAIL resistance results in cancer progression: a TRAIL to perdition? Oncogene 2006; 25: 7333–7335.

    Article  CAS  PubMed  Google Scholar 

  30. Frese S, Frese-Schaper M, Andres AC, Miescher D, Zumkehr B, Schmid RA . Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer Res 2006; 66: 5867–5874.

    Article  CAS  PubMed  Google Scholar 

  31. Butler LM, Liapis V, Bouralexis S, Welldon K, Hay S, Thai le M et al. The histone deacetylase inhibitor, suberoylanilide hydroxamic acid, overcomes resistance of human breast cancer cells to Apo2L/TRAIL. Int J Cancer 2006; 119: 944–954.

    Article  CAS  PubMed  Google Scholar 

  32. VanOosten RL, Moore JM, Karacay B, Griffith TS . Histone deacetylase inhibitors modulate renal cell carcinoma sensitivity to TRAIL/Apo-2L-induced apoptosis by enhancing TRAIL-R2 expression. Cancer Biol Ther 2005; 4: 1104–1112.

    Article  CAS  PubMed  Google Scholar 

  33. Earel Jr JK, VanOosten RL, Griffith TS . Histone deacetylase inhibitors modulate the sensitivity of tumor necrosis factor-related apoptosis-inducing ligand-resistant bladder tumor cells. Cancer Res 2006; 66: 499–507.

    Article  CAS  PubMed  Google Scholar 

  34. VanOosten RL, Earel Jr JK, Griffith TS . Enhancement of Ad5-TRAIL cytotoxicity against renal cell carcinoma with histone deacetylase inhibitors. Cancer Gene Ther 2006; 13: 628–632.

    Article  CAS  PubMed  Google Scholar 

  35. Tomasetti M, Andera L, Alleva R, Borghi B, Neuzil J, Procopio A . Alpha-tocopheryl succinate induces DR4 and DR5 expression by a p53-dependent route: implication for sensitisation of resistant cancer cells to TRAIL apoptosis. FEBS Lett 2006; 580: 1925–1931.

    Article  CAS  PubMed  Google Scholar 

  36. Wenger T, Mattern J, Penzel R, Gassler N, Haas TL, Sprick MR et al. Specific resistance upon lentiviral TRAIL transfer by intracellular retention of TRAIL receptors. Cell Death Differ 2006; 13: 1740–1751.

    Article  CAS  PubMed  Google Scholar 

  37. Terzioglu E, Bisgin A, Sanlioglu AD, Ulker M, Yazisiz V, Tuzuner S et al. Concurrent gene therapy strategies effectively destroy synoviocytes of patients with rheumatoid arthritis. Rheumatology (Oxford) 2007; 46: 783–789.

    Article  CAS  Google Scholar 

  38. Hesry V, Piquet-Pellorce C, Travert M, Donaghy L, Jegou B, Patard JJ et al. Sensitivity of prostate cells to TRAIL-induced apoptosis increases with tumor progression: DR5 and caspase 8 are key players. Prostate 2006; 66: 987–995.

    Article  CAS  PubMed  Google Scholar 

  39. Riccioni R, Pasquini L, Mariani G, Saulle E, Rossini A, Diverio D et al. TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL. Haematologica 2005; 90: 612–624.

    CAS  PubMed  Google Scholar 

  40. Vogler M, Durr K, Jovanovic M, Debatin KM, Fulda S . Regulation of TRAIL-induced apoptosis by XIAP in pancreatic carcinoma cells. Oncogene 2007; 26: 248–257.

    Article  CAS  PubMed  Google Scholar 

  41. Nakao K, Hamasaki K, Ichikawa T, Arima K, Eguchi K, Ishii N . Survivin downregulation by siRNA sensitizes human hepatoma cells to TRAIL-induced apoptosis. Oncol Rep 2006; 16: 389–392.

    Article  CAS  PubMed  Google Scholar 

  42. Koksal IT, Sanlioglu AD, Karacay B, Griffith TS, Sanlioglu S . TRAIL-R4 decoy receptor gene expression is correlated with high Gleason scores, PSA recurrence and decreased survival in patients with prostate carcinoma. Urol Oncol (in press).

Download references

Acknowledgements

This research is funded by the Akdeniz University Scientific Research Project Administration Division and the Health Science Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Sanlioglu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sanlioglu, A., Karacay, B., Koksal, I. et al. DcR2 (TRAIL-R4) siRNA and adenovirus delivery of TRAIL (Ad5hTRAIL) break down in vitro tumorigenic potential of prostate carcinoma cells. Cancer Gene Ther 14, 976–984 (2007). https://doi.org/10.1038/sj.cgt.7701087

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7701087

Keywords

This article is cited by

Search

Quick links