Gossypol induces apoptosis in human PC-3 prostate cancer cells by modulating caspase-dependent and caspase-independent cell death pathways.
The rate of gossypol-induced apoptosis does not correlate very well with the same dose of gossypol-induced cell growth inhibition, indicating an anti-proliferative effect of gossypol. Using a co-immunoprecipitation assay, it was observed that the level of Bcl-X(L) protein bound to Bax was clearly lower than that of Bcl-2 protein at 5 micro M of gossypol treatment, and the level of Bim protein bound to Bcl-X(L) was lowered at 20 micro M of gossypol treatment for 24 h, implicating that gossypol inhibits the heterodimerization of Bcl-X(L) with Bax and Bim. Gossypol-induced apoptosis is partly suppressed by as low as 0.5 micro M, but not abolished by as high as 50 micro M of a broad range caspase inhibitor, Z-VAD-FMK, suggesting that gossypol-induced apoptosis is both caspase-dependent and -independent. Furthermore, the release of apoptosis inducing factor (AIF), which triggers caspase-independent apoptosis, from mitochondria to cytosol was observed in PC-3 cells exposed to gossypol treatment. In conclusion, gossypol inhibits the proliferation and induces apoptosis in PC-3 cells. Gossypol-induced apoptosis is, at least, through inhibiting the heterodimerization of Bcl-X(L)/Bcl-2 with pro-apoptosis molecules, followed by a caspase-dependent and -independent process which involves the release of AIF from the mitochondria to cytosol.
Zhang
Manchao
M
Department of Biochemistry and Molecular Pharmacology, West Virginia University, Morgantown, WV 26506, USA. mzhang2@hsc.wvu.edu
Liu
Hongpeng
H
Tian
Zhenkun
Z
Griffith
Brian N
BN
Ji
Min
M
Li
Q Quentin
QQ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003272:Contraceptive Agents, Male / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494829:AIFM1 protein, human; D000590:Amino Acid Chloromethyl Ketones; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D061945:Caspase Inhibitors; D003272:Contraceptive Agents, Male; D015853:Cysteine Proteinase Inhibitors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases; D006072:Gossypol