title: Se-methylselenocysteine induces apoptosis through caspase activation and Bax cleavage mediated by calpain in SKOV-3 ovarian cancer cells.
abstract: Se-methylselenocysteine (Se-MSC) is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis, but its mechanism of action is still not well understood. The present study was designed to assess the mechanism of Se-MSC on the induction of apoptosis in SKOV-3 ovarian cancer cells. Se-MSC displayed strong inhibitory effects on cell proliferation and viability of SKOV-3 cells in dose and time dependent manners and induced apoptosis. Investigation of the mechanism of Se-MSC-induced apoptosis revealed that treatment with Se-MSC produced morphological features of apoptosis and DNA fragmentation. This was associated with caspase-3 activation and cleavage of poly(ADP-ribose) polymerase and phospholipase C-gamma1 proteins. However, SKOV-3 cells treated with Se-MSC did not demonstrate cytochrome c accumulation in the cytosol during apoptosis induction. Pretreatment of cells with the caspase inhibitors (z-VAD-fmk and DEVD-CHO) prevented Se-MSC-induced apoptosis. These results suggested that Se-MSC induces apoptosis through cytochrome c-independent caspase-3 activation in SKOV-3 cells. In late stage of apoptosis, p18kDa fragment of Bax was generated with the down-regulation of the expressions of survivin, X-linked inhibitor of apoptosis protein, and human inhibitor of apoptosis protein 1 following Se-MSC treatment, suggesting that the modulation of Bax and IAP (inhibitors of apoptosis) family proteins play some role in Se-MSC-mediated apoptosis. Pre-treatments of z-VAD-fmk and the calpain inhibitor, calpeptin inhibited Bax cleavage. These results suggested that Bax cleavage is mediated by calpain, and calpain activation may be a caspase-dependent one. Taken together, the chemopreventive effects of Se-MSC may be related in part to the caspase-3 activation, the down-regulation of IAP family proteins, and Bax cleavage mediated by caspase-dependent calpain activation.
authors.affiliation: Department of Gynecology and Obstetrics, Keimyung University School of Medicine, Daegu, South Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Yeo
authors.forename: Soon-Do
authors.initials: SD
authors.lastname: Cha
authors.forename: Chi-Heum
authors.initials: CH
authors.lastname: Cho
authors.forename: Sang-Pyo
authors.initials: SP
authors.lastname: Kim
authors.forename: Jae-We
authors.initials: JW
authors.lastname: Cho
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Baek
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Suh
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Jong-Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Seong-Il
authors.initials: SI
authors.lastname: Suh
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000502:physiology*; D020169:Caspases / Q000502:physiology*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011506:Proteins / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D017279:Selenocysteine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
chemical_list: D016588:Anticarcinogenic Agents; C494826:BAX protein, human; D003574:Cytochrome c Group; D051034:Inhibitor of Apoptosis Proteins; D016566:Organoselenium Compounds; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D017279:Selenocysteine; D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; D020169:Caspases; D003545:Cysteine; C002979:selenomethylselenocysteine