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J. Biol. Chem. 277 (25): 22320-22329

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

An Inducible Pathway for Degradation of FLIP Protein Sensitizes Tumor Cells to TRAIL-induced Apoptosis*

Youngsoo Kim, Nanjoo SuhDagger , Michael SpornDagger , and John C. Reed§

From The Burnham Institute, La Jolla, California 92037 and the Dagger  Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755

TRAIL (Apo2 ligand) is a member of the tumor necrosis factor (TNF) family of cytokines that induces apoptosis. Because TRAIL preferentially kills tumor cells, sparing normal tissues, interest has emerged in applying this biological factor for cancer therapy in humans. However, not all tumors respond to TRAIL, raising questions about resistance mechanisms. We demonstrate here that a variety of natural and synthetic ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma ) sensitize tumor but not normal cells to apoptosis induction by TRAIL. PPARgamma ligands selectively reduce levels of FLIP, an apoptosis-suppressing protein that blocks early events in TRAIL/TNF family death receptor signaling. Both PPARgamma agonists and antagonists displayed these effects, regardless of the levels of PPARgamma expression and even in the presence of a PPARgamma dominant-negative mutant, indicating a PPARgamma -independent mechanism. Reductions in FLIP and sensitization to TRAIL-induced apoptosis were also not correlated with NF-kappa B, further suggesting a novel mechanism. PPARgamma modulators induced ubiquitination and proteasome-dependent degradation of FLIP, without concomitant reductions in FLIP mRNA. The findings suggest the existence of a pharmacologically regulated novel target of this class of drugs that controls FLIP protein turnover, and raise the possibility of combining PPARgamma modulators with TRAIL for more efficacious elimination of tumor cells through apoptosis.

* This work was supported by National Institutes of Health Grants CA 69381, CA55164, and CA78040 and by Susan G. Komen Foundation California Breast Cancer Research Program Grant 5FB-0170.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: The Burnham Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3100; Fax: 858-646-3194; E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Regulation of apoptosis: the ubiquitous way.
Y. YANG and X. YU (2003)
FASEB J 17, 790-799
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A Peroxisome Proliferator-activated Receptor-{gamma} Agonist and the p53 Rescue Drug CP-31398 Inhibit the Spontaneous Immortalization of Breast Epithelial Cells.
B.-S. Herbert, V. P. Pearce, L. S. Hynan, D. M. LaRue, W. E. Wright, L. Kopelovich, and J. W. Shay (2003)
Cancer Res. 63, 1914-1919
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Synthetic Triterpenoids Enhance Transforming Growth Factor {beta}/Smad Signaling.
N. Suh, A. B. Roberts, S. Birkey Reffey, K. Miyazono, S. Itoh, P. t. Dijke, E. H. Heiss, A. E. Place, R. Risingsong, C. R. Williams, et al. (2003)
Cancer Res. 63, 1371-1376
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Erythroid Differentiation Sensitizes K562 Leukemia Cells to TRAIL-Induced Apoptosis by Downregulation of c-FLIP.
V. Hietakangas, M. Poukkula, K. M. Heiskanen, J. T. Karvinen, L. Sistonen, and J. E. Eriksson (2003)
Mol. Cell. Biol. 23, 1278-1291
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Pediatric Acute Lymphoblastic Leukemia.
W. L. Carroll, D. Bhojwani, D.-J. Min, E. Raetz, M. Relling, S. Davies, J. R. Downing, C. L. Willman, and J. C. Reed (2003)
Hematology 2003, 102-131
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The Long Form of FLIP Is an Activator of Caspase-8 at the Fas Death-inducing Signaling Complex.
O. Micheau, M. Thome, P. Schneider, N. Holler, J. Tschopp, D. W. Nicholson, C. Briand, and M. G. Grutter (2002)
J. Biol. Chem. 277, 45162-45171
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Shiga-like Toxin Inhibition of FLICE-like Inhibitory Protein Expression Sensitizes Endothelial Cells to Bacterial Lipopolysaccharide-induced Apoptosis.
R. D. Erwert, R. K. Winn, J. M. Harlan, and D. D. Bannerman (2002)
J. Biol. Chem. 277, 40567-40574
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TRAIL-induced apoptosis of authentic myeloma cells does not correlate with the procaspase-8/cFLIP ratio.
A. Spencer, S.-L. Yeh, K. Koutrevelis, C. Baulch-Brown ;, N. Mitsiades, C. Mitsiades, K. C. Anderson, and S. P. Treon (2002)
Blood 100, 3049-3050
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The triterpenoid CDDO induces apoptosis in refractory CLL B cells.
I. M. Pedersen, S. Kitada, A. Schimmer, Y. Kim, J. M. Zapata, L. Charboneau, L. Rassenti, M. Andreeff, F. Bennett, M. B. Sporn, et al. (2002)
Blood 100, 2965-2972
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