title: Inhibitory effect of snake venom toxin from Vipera lebetina turanica on hormone-refractory human prostate cancer cell growth: induction of apoptosis through inactivation of nuclear factor kappaB.
abstract: We investigated whether the snake venom toxin (SVT) from Vipera lebetina turanica inhibits cell growth of human prostate cancer cells by inducing apoptosis and also studied possible signaling pathways involved in this cell death. SVT inhibited growth of PC-3 and DU145 cells, androgen-independent prostate cancer cells, but not LNCaP cells, a human androgen-dependent prostate cancer cell. Cells were arrested in the G(2)-M phase by SVT with a concomitant decrease in the expression of the G(2)-M phase regulatory protein cyclin B1 and were also arrested in the G(1)-S phase with decreasing expression of cyclin-dependent kinase 4, cyclin D1 and cyclin E. In addition to the growth-inhibitory effect, SVT increased the induction of apoptotic cell death. Untreated PC-3 cells show high DNA binding activity of nuclear factor kappaB (NF-kappaB), an antiapoptotic transcriptional factor, but this was inhibited by SVT and accompanied by a significant inhibition of p50 translocation into the nucleus, as well as phosphorylation of inhibitory kappaB. Consistent with the induction of apoptosis and inhibition of NF-kappaB, this toxin increased the expression of proapoptotic proteins such as p53, Bax, caspase-3, and caspase-9, but down-regulated antiapoptotic protein Bcl-2. However, SVT did not show an inhibitory effect on cell growth and caspase-3 activity in cells carrying mutant p50 and inhibitory kappaB kinase plasmids. Confocal microscopy analysis showed that SVT is taken up into the nucleus of the cells. These findings suggest that a nanogram concentration range of SVT from V. lebetina turanica could inhibit hormone-refractory human prostate cancer cell growth, and the effect may be related to NF-kappaB signal-mediated induction of apoptosis.
authors.affiliation: College of Pharmacy, Chungbuk National University, 48 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 Korea.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Chae
authors.forename: Soon Ok
authors.initials: SO
authors.lastname: Moon
authors.forename: Jae Woong
authors.initials: JW
authors.lastname: Lee
authors.forename: Ho Sueb
authors.initials: HS
authors.lastname: Song
authors.forename: Dong Cheul
authors.initials: DC
authors.lastname: Moon
authors.forename: Sang Sun
authors.initials: SS
authors.lastname: Kang
authors.forename: Young Ee
authors.initials: YE
authors.lastname: Kwon
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002467:Cell Nucleus; D016213:Cyclins / Q000378:metabolism; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D012910:Snake Venoms / Q000494:pharmacology*; D014118:Toxins, Biological / Q000494:pharmacology*; D017819:Viperidae
chemical_list: D016213:Cyclins; D016328:NF-kappa B; D012910:Snake Venoms; D014118:Toxins, Biological; D020169:Caspases