Open Access

Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs

  • Authors:
    • Ying Huang
    • Xiang Yang
    • Tianrui Xu
    • Qinghong Kong
    • Yaping Zhang
    • Yuehai Shen
    • Yunlin Wei
    • Guanlin Wang
    • Kwen-Jen Chang
  • View Affiliations

  • Published online on: May 16, 2016     https://doi.org/10.3892/ijo.2016.3525
  • Pages: 153-163
  • Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The discovery of the TRAIL protein and its death receptors DR4/5 changed the horizon of cancer research because TRAIL specifically kills cancer cells. However, the validity of TRAIL-based cancer therapies has yet to be established, as most cancer cells are TRAIL-resistant. In this report, we demonstrate that TRAIL-resistance of many cancer cell lines can be overcome after siRNA- or rocaglamide-mediated downregulation of c-FLIP expression and simultaneous inhibition of IAPs activity using AT406, a pan-antagonist of IAPs. Combined triple actions of the TRAIL, the IAPs inhibitor, AT406, and the c-FLIP expression inhibitor, rocaglamide (ART), markedly improve TRAIL-induced apoptotic effects in most solid cancer cell lines through the activation of an extrinsic apoptosis pathway. Furthermore, this ART combination does not harm normal cells. Among the 18 TRAIL-resistant cancer cell lines used, 15 cell lines become sensitive or highly sensitive to ART, and two out of three glioma cell lines exhibit high resistance to ART treatment due to very low levels of procaspase-8. This study provides a rationale for the development of TRAIL-induced apoptosis-based cancer therapies.
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July-2016
Volume 49 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Huang Y, Yang X, Xu T, Kong Q, Zhang Y, Shen Y, Wei Y, Wang G and Chang K: Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs. Int J Oncol 49: 153-163, 2016.
APA
Huang, Y., Yang, X., Xu, T., Kong, Q., Zhang, Y., Shen, Y. ... Chang, K. (2016). Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs. International Journal of Oncology, 49, 153-163. https://doi.org/10.3892/ijo.2016.3525
MLA
Huang, Y., Yang, X., Xu, T., Kong, Q., Zhang, Y., Shen, Y., Wei, Y., Wang, G., Chang, K."Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs". International Journal of Oncology 49.1 (2016): 153-163.
Chicago
Huang, Y., Yang, X., Xu, T., Kong, Q., Zhang, Y., Shen, Y., Wei, Y., Wang, G., Chang, K."Overcoming resistance to TRAIL-induced apoptosis in solid tumor cells by simultaneously targeting death receptors, c-FLIP and IAPs". International Journal of Oncology 49, no. 1 (2016): 153-163. https://doi.org/10.3892/ijo.2016.3525