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Inhibition of the Phosphatidylinositol 3'-Kinase Pathway Promotes Autocrine Fas-Induced Death of Phosphatase and Tensin Homologue–Deficient Prostate Cancer Cells

¹ The Prostate Centre, Vancouver General Hospital; Departments of ² Surgery and ³ Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Christopher J. Ong, Department of Surgery, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6. Phone: 604-875-5555, ext. 63120; Fax: 604-875-5654; E-mail: chriso{at}interchange.ubc.ca.

Rationally designed therapeutics that target the phosphatidylinositol 3'-kinase (PI3K) cell survival pathway are currently in preclinical and clinical development for cancer therapy. Drugs targeting the PI3K pathway aim to inhibit proliferation, promote apoptosis, and enhance chemosensitivity and radiosensitivity of cancer cells. The phosphatase and tensin homologue (PTEN) phosphatidylinositol 3'-phosphatase is a key negative regulator of the PI3K pathway. Inactivation of the PTEN tumor suppressor results in constitutive activation of the PI3K pathway and is found in 50% of advanced prostate cancers, which correlates with a high Gleason score and poor prognosis. Inhibition of the PI3K pathway leads to apoptosis of prostate cancer cells; however, the precise mechanism by which this occurs is unknown. Here we report that apoptotic cell death of PTEN-deficient LNCaP and PC3 prostate cancer cells induced by the PI3K inhibitor LY294002 can be abrogated by disrupting Fas/Fas ligand (FasL) interactions with recombinant Fas:Fc fusion protein or FasL neutralizing antibody (Nok-1), or by expressing dominant-negative Fas-associated death domain. Furthermore, we find that apoptosis induced by expression of wild-type PTEN, driven by a tetracycline-inducible expression system in LNCaP cells, can be inhibited by blocking Fas/FasL interaction using Fas:Fc or Nok-1. These data show that apoptosis induced by blockade of the PI3K pathway in prostate tumor cells is mediated by an autocrine Fas/FasL apoptotic mechanism and the Fas apoptotic pathway is both necessary and sufficient to mediate apoptosis by PI3K inhibition. (Cancer Res 2006; 66(9): 4781-8)

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