Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells

Yi Huang; Yong Fang; Jinmin Wu; Jennifer M Dziadyk; Xueming Zhu; Meihua Sui; Weimin Fan

doi:10.1158/1535-7163.271.3.3

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Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells

Journal article

Open access

Peer reviewed

Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells

Yi Huang, Yong Fang, Jinmin Wu, Jennifer M Dziadyk, Xueming Zhu, Meihua Sui and Weimin Fan

Molecular cancer therapeutics, Vol.3(3), pp.271-277

03/2004

DOI: 10.1158/1535-7163.271.3.3

PMID: 15026547

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Abstract

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.

Apoptosis

Flow Cytometry

Mitosis

Mutation

Signal Transduction

Transfection

Alkaloids - pharmacology

Blotting, Western

Cell Line, Tumor

Cell Nucleus - metabolism

DNA Fragmentation

Dose-Response Relationship, Drug

G2 Phase

Gene Deletion

Genes, Dominant

Glucocorticoids - metabolism

Glutathione Transferase - metabolism

Humans

I-kappa B Proteins - metabolism

Microtubules - metabolism

NF-kappa B - metabolism

NF-KappaB Inhibitor alpha

Precipitin Tests

Vinca - metabolism

Details

Title: Subtitle: Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells
Creators: Yi Huang - Medical University of South Carolina
Yong Fang
Jinmin Wu
Jennifer M Dziadyk
Xueming Zhu
Meihua Sui
Weimin Fan
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.3(3), pp.271-277
DOI: 10.1158/1535-7163.271.3.3
PMID: 15026547
NLM abbreviation: Mol Cancer Ther
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: CA 92880 / NCI NIH HHS CA 82440 / NCI NIH HHS
Language: English
Date published: 03/2004
Academic Unit: Internal Medicine
Record Identifier: 9984383277402771

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