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¹ Department of Urology and Kansas Cancer Institute, The University of Kansas Medical Center, Kansas City, KS and ² Department of Medicine, University of Texas Medical Branch, Galveston, TX

Requests for Reprints: Benyi Li, KUMC Urology, Mail Stop 3016, 3901 Rainbow Boulevard, Lied 1042, Kansas City, KS 66160. Phone: (913) 588-4773; Fax: (913) 588-7625. E-mail: bli{at}kumc.edu

Prostate cancer is a major health threat for American men. Therefore, the development of effective therapeutic options is an urgent issue for prostate cancer treatment. In this study, we evaluated the effect of glycogen synthase kinase-3ß (GSK-3ß) suppression on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human prostate cancer cell lines. In the presence of lithium chloride (LiCl) or SB216763, the GSK-3ß inhibitors, TRAIL-induced cell death was dramatically enhanced, and the enhanced cell death was an augmented apoptotic response evidenced by increased Annexin V labeling and caspase-3 activation. GSK-3ß gene silencing mediated by a small interference RNA (siRNA) duplex also sensitized the cells to TRAIL, confirming the specificity of GSK-3ß suppression. Importantly, TRAIL stimulation increased GSK-3ß tyrosine phosphorylation at Y216, suggesting that GSK-3ß is activated by TRAIL. Furthermore, TRAIL sensitization was associated with increased proteolytic procession of caspase-8 and its downstream target BID, and z-IETD-FMK, the inhibitor specific to active caspase-8 totally blocked LiCl-induced TRAIL sensitization. Finally, Trichodion, a potent nuclear factor-B (NF-B) inhibitor, could not affect LiCl-induced TRAIL sensitization, although GSK-3ß inhibitors significantly blocked TRAIL-reduced NF-B activity in prostate cancer cells. These results indicate that GSK-3ß suppression sensitizes prostate cancer cells to TRAIL-induced apoptosis that is dependent on caspase-8 activities but independent of NF-B activation, and suggest that a mechanism involving GSK-3ß activation may be responsible for TRAIL resistance in prostate cancer cells.

Key Words: prostate cancer • lithium chloride • GSK-3ß • apoptosis • TRAIL • death receptor • caspase-8 • NF-B • reporter gene assay

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.

Grant support: William L.Valk Endowment, Mason's Foundation and Start-up fund from the Kansas Cancer Institute for B. Li, and grants from NIH (HL45317) and AHA SDG to J. Du.

Received 6/ 5/03; revised 7/ 7/03; accepted 8/ 5/03.

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