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Molecular and Cellular Biology, October 2004, p. 8541-8555, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8541-8555.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Direct Repression of FLIP Expression by c-myc Is a Major Determinant of TRAIL Sensitivity

M. Stacey Ricci,1 Zhaoyu Jin,1 Michael Dews,2 Duonan Yu,2 Andrei Thomas-Tikhonenko,2 David T. Dicker,1 and Wafik S. El-Deiry1*

Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Departments of Medicine, Genetics and Pharmacology, University of Pennsylvania School of Medicine,1 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania Philadelphia, Pennsylvania2

Received 28 November 2003/ Returned for modification 16 January 2004/ Accepted 1 July 2004

Tumor necrosis factor alpha (TNF-{alpha})-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-{alpha} family of death receptor ligands and holds great therapeutic potential as a tumor cell-specific cytotoxic agent. Using a panel of established tumor cell lines and normal cells, we found a significant difference between the number of TRAIL-sensitive cells expressing high levels of c-myc and TRAIL-resistant cells expressing low levels of c-myc (P < 0.05, n = 19). We also found a direct linear correlation between c-myc levels and TRAIL sensitivity in TRAIL-sensitive cell lines (r = 0.94, n = 6). Overexpression of c-myc or activation of a myc-estrogen receptor (ER) fusion sensitized TRAIL-resistant cells to TRAIL. Conversely, small interfering RNA (siRNA)-mediated knockdown of c-myc significantly reduced both c-myc expression and TRAIL-induced apoptosis. The gene encoding the inhibitor of caspase activation, FLICE inhibitory protein (FLIP), appears to be a direct target of c-myc-mediated transcriptional repression. Overexpression of c-myc or activation of myc-estrogen receptor (ER) decreased FLIP levels both in cell culture and in mouse models of c-myc-induced tumorigenesis, while knocking down c-myc using siRNA increased FLIP expression. Chromatin immunoprecipitation and luciferase reporter analyses showed that c-myc binds and represses the human FLIP promoter. c-myc expression enhanced TRAIL-induced caspase 8 cleavage and FLIP cleavage at the death-inducing signaling complex. Combined siRNA-mediated knockdown of FLIP and c-myc resensitized cells to TRAIL. Therefore, c-myc down-regulation of FLIP expression provides a universal mechanism to explain the ability of c-myc to sensitize cells to death receptor stimuli. In addition, identification of c-myc as a major determinant of TRAIL sensitivity provides a potentially important screening tool for identification of TRAIL-sensitive tumors.

* Corresponding author. Mailing address: Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 437A, Philadelphia, PA 19104. Phone: (215) 898-9015. Fax: (215) 573-9139. E-mail: wafik{at}mail.med.upenn.edu.

Molecular and Cellular Biology, October 2004, p. 8541-8555, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8541-8555.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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