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:

A double tyrosine phosphorylation of P68 RNA helicase confers resistance to TRAIL-induced apoptosis

Oncogene volume 26, pages 6082–6092 (2007)Cite this article

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent with the capability of inducing apoptosis specifically in tumor cells. However, cancer cells of many cancer types developed TRAIL resistance, limiting the applications of TRAIL in cancer therapies. We show here that p68 acquires a double tyrosine phosphorylation at Y593 and Y595 in TRAIL-resistant T98G glioblastoma cells. The double phosphorylations are induced by platelet-derived growth factor autocrine loop. The double phosphorylation mediates resistance to TRAIL-induced apoptosis. Our data suggest that the phosphorylated p68 protects the cells from programmed cell death by preventing procaspase-8 from proteolytic cleavage. The double-phosphorylated p68 may also confer apoptosis resistance by upregulation of X-chromosome-linked inhibitor apoptosis protein-associated factor 1. In addition, exogenous expression of p68 mutant that carries mutations at the phosphorylation sites (Y593/595F) dramatically sensitizes TRAIL-resistant cells to TRAIL-induced apoptosis, suggesting a potential therapeutic strategy to overcome TRAIL resistance.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

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

Similar content being viewed by others

References

  • Aggarwal BB, Bhardwaj U, Takada Y . (2004). Regulation of TRAIL-induced apoptosis by ectopic expression of antiapoptotic factors. Vitam Horm 67: 453–483.

    Article  CAS  PubMed  Google Scholar 

  • Boatright KM, Salvesen GS . (2003). Mechanisms of caspase activation. Curr Opin Cell Biol 15: 725–731.

    Article  CAS  PubMed  Google Scholar 

  • Bockbrader KM, Tan M, Sun Y . (2005). A small molecule Smac-mimic compound induces apoptosis and sensitizes TRAIL- and etoposide-induced apoptosis in breast cancer cells. Oncogene 24: 7381–7388.

    Article  CAS  PubMed  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  PubMed  Google Scholar 

  • Causevic M, Hislop RG, Kernohan NM, Carey FA, Kay RA, Steele RJ et al. (2001). Overexpression and poly-ubiquitylation of the DEAD-box RNA helicase p68 in colorectal tumours. Oncogene 20: 7734–7743.

    Article  CAS  PubMed  Google Scholar 

  • Clarke N, Nebbioso A, Altucci L, Gronemeyer H . (2005). TRAIL: at the center of drugable anti-tumor pathways. Cell Cycle 4: 914–918.

    Article  CAS  PubMed  Google Scholar 

  • Crawford L, Leppard K, Lane D, Harlow E . (1982). Cellular proteins reactive with monoclonal antibodies directed against simian virus 40 T-antigen. J Virol 42: 612–620.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deng Y, Lin Y, Wu X . (2002). TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev 16: 33–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG . (2000). Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 70: 113–122.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Grotzer MA, Eggert A, Zuzak TJ, Janss AJ, Marwaha S, Wiewrodt BR et al. (2000). Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 19: 4604–4610.

    Article  CAS  PubMed  Google Scholar 

  • Hao C, Beguinot F, Condorelli G, Trencia A, Van Meir EG, Yong VW et al. (2001). Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in human malignant glioma cells. Cancer Res 61: 1162–1170.

    CAS  PubMed  Google Scholar 

  • Holcik M, Gibson H, Korneluk RG . (2001). XIAP: apoptotic brake and promising therapeutic target. Apoptosis 6: 253–261.

    Article  CAS  PubMed  Google Scholar 

  • Hwang RF, Yokoi K, Bucana CD, Tsan R, Killion JJ, Evans DB et al. (2003). Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model. Clin Cancer Res 9: 6534–6544.

    CAS  PubMed  Google Scholar 

  • Kim Y, Seol DW . (2003). TRAIL, a mighty apoptosis inducer. Mol Cell 15: 283–293.

    CAS  Google Scholar 

  • Lane DP, Hoeffler WK . (1980). SV40 large T shares an antigenic determinant with a cellular protein of molecular weight 68, 000. Nature 288: 167–170.

    Article  CAS  PubMed  Google Scholar 

  • Leaman DW, Chawla-Sarkar M, Vyas K, Reheman M, Tamai K, Toji S et al. (2002). Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis. J Biol Chem 277: 28504–28511.

    Article  CAS  PubMed  Google Scholar 

  • LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P et al. (2002). Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 8: 274–281.

    Article  CAS  PubMed  Google Scholar 

  • Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D et al. (2001). Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nat Cell Biol 3: 128–133.

    Article  CAS  PubMed  Google Scholar 

  • Nesterov A, Lu X, Johnson M, Miller GJ, Ivashchenko Y, Kraft AS . (2001). Elevated AKT activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis. J Biol Chem 276: 10767–10774.

    Article  CAS  PubMed  Google Scholar 

  • Ng KC, Campos EI, Martinka M, Li G . (2004). XAF1 expression is significantly reduced in human melanoma. J Invest Dermatol 123: 1127–1134.

    Article  CAS  PubMed  Google Scholar 

  • Nicol SM, Causevic M, Prescott AR, Fuller-Pace FV . (2000). The nuclear DEAD box RNA helicase p68 Interacts with the nucleolar protein fibrillarin and colocalizes specifically in nascent nucleoli during telophase. Exp Cell Res 257: 272–280.

    Article  CAS  PubMed  Google Scholar 

  • Potapova O, Fakhrai H, Baird S, Mercola D . (1996). Platelet-derived growth factor-B/v-sis confers a tumorigenic and metastatic phenotype to human T98G glioblastoma cells. Cancer Res 56: 280–286.

    CAS  PubMed  Google Scholar 

  • Roth W, Reed JC . (2004). FLIP protein and TRAIL-induced apoptosis. Vitam Horm 67: 189–206.

    Article  CAS  PubMed  Google Scholar 

  • Soldani C, Scovassi AI . (2002). Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: an update. Apoptosis 7: 321–328.

    Article  CAS  PubMed  Google Scholar 

  • Stevenson RJ, Hamilton SJ, MacCallum DE, Hall PA, Fuller-Pace FV . (1998). Expression of the ‘dead box’ RNA helicase p68 is developmentally and growth regulated and correlates with organ differentiation/maturation in the fetus. J Pathol 184: 351–359.

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi H, Kanzawa T, Kondo Y, Kondo S . (2004). Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells. Br J Cancer 90: 1069–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Van Geelen CM, de Vries EG, de Jong S . (2004). Lessons from TRAIL-resistance mechanisms in colorectal cancer cells: paving the road to patient-tailored therapy. Drug Resist Updat 7: 345–358.

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Lenardo MJ . (2000). Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies. J Cell Sci 113 (Part 5): 753–757.

    CAS  PubMed  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  PubMed  Google Scholar 

  • Yang L, Lin C, Liu ZR . (2005). Phosphorylations of DEAD box p68 RNA helicase are associated with cancer development and cell proliferation. Mol Cancer Res 3: 355–363.

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Lin C, Liu ZR . (2006). P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell 127: 139–155.

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Merchant MS, Romero ME, Tsokos M, Wexler LH, Kontny U et al. (2003). Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB. Cancer Res 63: 1122–1129.

    CAS  PubMed  Google Scholar 

  • Zhang L, Fang B . (2005). Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12: 228–237.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Roger Bridgeman for antibody p68-rgg production. We also thank Birgit Neuhaus for assistance in confocal imaging. This manuscript is greatly improved by critical comments from Jenny J Yang, Julian A Johnson, Christie Carter and Heena Dey. This work is supported in part by research grants from National Institute of Health (GM063874) and Georgia Cancer Coalition to ZR Liu. L Yang is supported by MBD fellowship, GSU.

Author information

Authors and Affiliations

  1. Department of Biology, Georgia State University, Atlanta, GA, USA

    L Yang, C Lin, S Zhao & Z-R Liu

  2. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    S-Y Sun

Authors
  1. L Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S-Y Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z-R Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z-R Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, L., Lin, C., Sun, SY. et al. A double tyrosine phosphorylation of P68 RNA helicase confers resistance to TRAIL-induced apoptosis. Oncogene 26, 6082–6092 (2007). https://doi.org/10.1038/sj.onc.1210427

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210427

Keywords

This article is cited by

Search

Advanced search

Quick links