title: Inhibition of the phosphatidylinositol 3'-kinase pathway promotes autocrine Fas-induced death of phosphatase and tensin homologue-deficient prostate cancer cells.
abstract: 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 approximately 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.
authors.affiliation: The Prostate Centre, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jerod
authors.initials: J
authors.lastname: Bertram
authors.forename: James W
authors.initials: JW
authors.lastname: Peacock
authors.forename: Clara
authors.initials: C
authors.lastname: Tan
authors.forename: Alice L-F
authors.initials: AL
authors.lastname: Mui
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chung
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002867:Chromones; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D019014:fas Receptor; C505533:FADD protein, human; C505661:FASLG protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494929:PTEN protein, human