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Research Articles: Therapeutics, Targets, and Development

Chemotherapeutic drugs sensitize cancer cells to TRAIL-mediated apoptosis: up-regulation of DR5 and inhibition of Yin Yang 1

¹ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; ² Department of Clinical Virology, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece; ³ Hospital de Infectologia, CMN "La Raza," UIM en Infectologia e Immunologia, Mexico D.F., Mexico; and ⁴ Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

Requests for reprints: Benjamin Bonavida, Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1747. Phone: 310-825-2233; Fax: 310-206-3865. E-mail: bbonavida{at}mednet.ucla.edu

Abstract

Several chemotherapeutic drugs in combination with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) result in reversal of resistance to TRAIL-mediated apoptosis through up-regulation of DR5 expression. The promoter of DR5 has one putative binding site for the transcription repressor Yin Yang 1 (YY1), and thus, we hypothesized that the sensitizing drugs may inhibit YY1. We have found that treatment of tumor cells with various chemotherapeutic drugs inhibited nuclear factor-B. We examined whether drugs also inhibit YY1 activity and whether YY1 inhibition correlates with up-regulation of DR5 expression and sensitization of cells to TRAIL-induced apoptosis. The TRAIL- and drug-resistant prostate carcinoma PC-3 cell line was treated with CDDP, VP-16, ADR, and vincristine. DR5 luciferase reporter constructs and small interfering RNA against YY1 were used to determine the role of YY1 in DR5 transcription. Pretreatment of PC-3 cells and other tumor cell lines with various chemotherapeutic drugs sensitized the cells to TRAIL-induced apoptosis concurrently with up-regulation of DR5 expression and inhibition of YY1 expression and its DNA-binding activity. The baseline luciferase activity in PC-3 cells transfected with the wild-type DR5 reporter was significantly augmented in cells transfected with DR5 constructs carrying deletions or mutation in the YY1-binding site. Treatment with drug enhanced DR5 wild-type luciferase activity, with no increase in cells transfected with the YY1-deleted or YY1-mutated constructs. Cells transfected with YY1 small interfering RNA showed up-regulation of DR5 expression and sensitization to TRAIL-mediated apoptosis. The findings provide evidence that drug-induced sensitization of tumor cells to TRAIL is mediated, in part, by inhibition of the transcription repressor YY1 and up-regulation of DR5 expression. Hence, YY1 may be a potential therapeutic target to reverse resistance to TRAIL-induced apoptosis. [Mol Cancer Ther 2007;6(4):1387–99]

Grant support: Department of Defense/U.S. Army grant DAMD 17-02-1-0023, University of California at Los Angeles Specialized Program of Research Excellence in Prostate Cancer grant P50 CA92131-01A1, University of California Institute for Mexico and the United States-Consejo Nacional de Ciencia y Tecnología (S. Huerta-Yepez), Fogarty Fellowships grant D43 TW00013-14 (S. Huerta-Yepez), and International Cancer Technology Transfer Fellowship of the International Union Against Cancer grant 60/2004 (S. Baritaki).

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.

⁵ Unpublished data.

Received 8/25/06; revised 11/ 9/06; accepted 2/ 8/07.

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