Involvement of protective autophagy in TRAIL resistance of apoptosis-defective tumor cells

Jie Han, Wen Hou, Leslie A. Goldstein, Caisheng Lu, Donna B. Stolz, Xiao Ming Yin, Hannah Rabinowich

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

Targeting TRAIL receptors with either recombinant TRAIL or agonistic DR4- or DR5-specific antibodies has been considered a promising treatment for cancer, particularly due to the preferential apoptotic susceptibility of tumor cells over normal cells to TRAIL. However, the realization that many tumors are unresponsive to TRAIL treatment has stimulated interest in identifying apoptotic agents that when used in combination with TRAIL can sensitize tumor cells to TRAIL-mediated apoptosis. Our studies suggest that various apoptosis defects that block TRAIL-mediated cell death at different points along the apoptotic signaling pathway shift the signaling cascade from default apoptosis toward cytoprotective autophagy. We also obtained evidence that inhibition of such a TRAIL-mediated autophagic response by specific knockdown of autophagic genes initiates an effective mitochondrial apoptotic response that is caspase-8-dependent. Currently, the molecular mechanisms linking disabled autophagy to mitochondrial apoptosis are not known. Our analysis of the molecular mechanisms involved in the shift from protective autophagy to apoptosis in response to TRAIL sheds new light on the negative regulation of apoptosis by the autophagic process and by some of its individual components.

Original languageEnglish (US)
Pages (from-to)19665-19677
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number28
DOIs
StatePublished - Jul 11 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Han, J., Hou, W., Goldstein, L. A., Lu, C., Stolz, D. B., Yin, X. M., & Rabinowich, H. (2008). Involvement of protective autophagy in TRAIL resistance of apoptosis-defective tumor cells. Journal of Biological Chemistry, 283(28), 19665-19677. https://doi.org/10.1074/jbc.M710169200