title: Induction of Fas clustering and apoptosis by coral prostanoid in human hormone-resistant prostate cancer cells.
abstract: Cyclopentenone prostaglandins (PGs) such as PGA1, PGA2 and delta12-PGJ2 have been shown to suppress tumor cell growth and to induce apoptosis in prostate cancer cells. Bromovulone III, which is isolated from the soft coral Clavularia viridis, is a cyclopentenone prostanoid. In this study, the anti-tumor activity as well as action mechanism of bromovulone III was identified in prostate cancer cells. Bromovulone III displayed anti-tumor activity of 30 to 100 times more effective than PGA1, PGA2 and delta12-PGJ2 in PC-3 cells. Several targets of caspases and Bcl-2 family of proteins were detected and the data demonstrated that bromovulone III induced the activation of caspase-8, -9 and -3, and Bid cleavage in which the caspase-8 activation occurred the first. Bromovulone III did not modify the protein levels of death receptors and ligands. Of note, the Fas clustering in PC-3 cells responsive to bromovulone III was observed by confocal immunofluorescence microscopy suggesting the involvement of Fas-mediated pathway. Bromovulone III also induced the cleavage of Mcl-1 in this study. The cleavage fragments (24, 19 and 17 kDa) may partly share the apoptotic insult. Although it has been suggested that Fas-mediated signaling may contribute to the caspase-8 activation induced by DNA-damaging agents; however, bromovulone III did not induce any DNA breakage, suggesting that bromovulone III-induced Fas/caspase-8-dependent signaling is not through the direct target on DNA damage. In summary, the data suggest that bromovulone III causes a rapid redistribution and clustering of Fas in PC-3 cells. Subsequently, the Fas event causes the activation and interaction of caspase-8/Bid/caspase-9 signaling cascades, and the activation of executor caspase-3.
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Sect. 1, Taipei, Taiwan, ROC.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chiang
authors.forename: Fan-Lu
authors.initials: FL
authors.lastname: Kung
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Huang
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Jia-Rong
authors.initials: JR
authors.lastname: Fan
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Shen
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053143:Caspase 2 / Q000378:metabolism; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053837:DNA Cleavage / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000737:chemistry / Q000494:pharmacology; D011453:Prostaglandins / Q000737:chemistry / Q000494:pharmacology*; D011454:Prostaglandins A / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D061945:Caspase Inhibitors; D009842:Oligopeptides; D011453:Prostaglandins; D011454:Prostaglandins A; D019253:Proto-Oncogene Proteins c-bcl-2; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; C515438:bromovulone III; C499810:delta(12)-prostaglandin J(2); D019014:fas Receptor; D053143:Caspase 2; C100008:prostaglandin A2; D015230:Prostaglandin D2; C100573:prostaglandin A1