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J. Biol. Chem., Vol. 283, Issue 28, 19665-19677, July 11, 2008

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Involvement of Protective Autophagy in TRAIL Resistance of Apoptosis-defective Tumor Cells^*

Jie Han¹, Wen Hou¹, Leslie A. Goldstein, Caisheng Lu, Donna B. Stolz, Xiao-Ming Yin, and Hannah Rabinowich^¶2

From the Departments of Pathology and Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and ^¶University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213

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.

Received for publication, December 13, 2007 , and in revised form, March 20, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants RO1 CA109285 and RO1 CA111786. This work was also supported by Department of Defense Grant BC063415 (to H. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: University of Pittsburgh Cancer Institute, The Hillman Cancer Center, Research Pavilion Rm. G17c, 5117 Centre Ave., Pittsburgh, PA 15213. Tel.: 412-623-3212; Fax: 412-623-1119; E-mail: rabinow{at}pitt.edu.

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