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Research Articles: Therapeutics, Targets, and Development

Epothilones induce human colon cancer SW620 cell apoptosis via the tubulin polymerization–independent activation of the nuclear factor-B/IB kinase signal pathway

¹ College of Pharmacy and Chungbuk BIT Research-Oriented University Consortium and ² College of Natural Science, Chungbuk National University, 410 SungBong-Ro, Heungduk-gu, Cheongju, Chungbuk, Korea; and ³ Cellular and Molecular Toxicology Laboratory, Korea Institute of Science and Technology, Cheongryang and ⁴ Department of Bioscience and Biotechnology, Konkuk University, Hwayang-dong 1, Gwangjin-gu, Seoul, Korea

Requests for reprints: Jin Tae Hong, College of Pharmacy, Chungbuk National University, 410 SungBong-Ro, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea. Phone: 82-43-261-2813; Fax: 82-43-268-2732. E-mail: jinthong{at}chungbuk.ac.kr

Abstract

Molecular mechanisms underlying epothilone-induced apoptotic cell death were investigated in SW620 human colon cancer cells. Treatment with epothilone B and D at different concentrations (1–100 nmol/L) dose-dependently inhibited cell growth and caused cell cycle arrest at G₂-M, which was followed by apoptosis. Consistent with this induction of apoptotic cell death, epothilone B and D enhanced the constitutional activation of nuclear factor-B (NF-B) via IB degradation through IB kinase (IKK and IKKß) activation, and this resulted in p50 and p65 translocation to the nucleus. Moreover, cells treated with sodium salicylic acid, an IKK inhibitor, or transiently transfected with mutant IKK and ß did not show epothilone-induced cell growth inhibition or p50 translocation, although p65 was still translocated to the nucleus. Treatment with epothilone B and D also enhanced ß-tubulin polymerization and the formation of p50/ß-tubulin complex. However, ß-tubulin polymerization was not inhibited in the cells treated by sodium salicylic acid or transiently transfected with mutant IKK and ß. Moreover, epothilone B and D increased the expressions of NF-B–dependent apoptotic cell death regulatory genes, i.e., Bax, p53, and the active form of caspase-3, but reduced Bcl-2 expression, and these actions were partially reversed by salicylic acid. In addition, caspase-3 inhibitor reduced epothilone B–induced cell death and NF-B activation. These findings suggest that the activation of NF-B/IKK signals plays an important role in the epothilone-induced apoptotic cell death of SW620 colon cancer cells in a tubulin polymerization–independent manner. [Mol Cancer Ther 2007;6(10):2786–97]

Grant support: Korea Research Foundation Grant funded by the Korean Government (Ministry of Education and Human Resource Development; The Regional Research Universities Program/Chungbuk BIT Research-Oriented University Consortium).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/16/07; revised 7/20/07; accepted 9/ 4/07.