Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells.
Antimicrotubule Vinca alkaloids, such as vinblastine and vincristine, interfere with the dynamics of microtubules and have shown significant cell killing activity in a variety of tumor cells through induction of apoptosis. The mechanism by which Vinca alkaloids induce apoptosis is not entirely clear. In this study, we found that glucocorticoids inhibit Vinca alkaloid-induced apoptosis without affecting G(2)-M arrest in human breast cancer BCap37 cells and human epidermoid tumor KB cells, suggesting that Vinca alkaloid-induced apoptosis may occur via a pathway independent of cell cycle arrest. Further analyses indicated that Vinca alkaloids cause significant degradation of IkappaBalpha, which in turn results in nuclear factor-kappaB (NF-kappaB) activation. Transfection of antisense IkappaBalpha in BCap37 cells sensitizes Vinca alkaloid-induced apoptosis. Moreover, in vitro kinase assays show that the activity of IkappaB kinase (IKK) was activated by Vinca alkaloids and was not affected by glucocorticoids. Stable transfection of dominant-negative deletional mutant IkappaBalpha, which is insensitive to IKK-mediated phosphorylation and degradation, resulted in the inhibition of Vinca alkaloid-induced NF-kappaB activation and reduced sensitivity of tumor cells to Vinca alkaloid-induced apoptosis. These findings suggest that the NF-kappaB/IkappaB signaling pathway may contribute to the mediation of Vinca alkaloid-induced apoptosis in human tumor cells.
Huang
Yi
Y
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
Fang
Yong
Y
Wu
Jinmin
J
Dziadyk
Jennifer M
JM
Zhu
Xueming
X
Sui
Meihua
M
Fan
Weimin
W
D000470:Alkaloids / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016195:G2 Phase; D017353:Gene Deletion; D005799:Genes, Dominant; D005938:Glucocorticoids / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011233:Precipitin Tests; D000091402:Prohibitins; D015398:Signal Transduction; D014162:Transfection; D031053:Vinca / Q000378:metabolism*
D000470:Alkaloids; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000717331:PHB2 protein, human; D000091402:Prohibitins; D000072000:NF-KappaB Inhibitor alpha; D005982:Glutathione Transferase