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Evidence-Based Complementary and Alternative Medicine
Volume 2013, Article ID 172548, 10 pages
http://dx.doi.org/10.1155/2013/172548
Research Article

Triptolide-Mediated Apoptosis by Suppression of Focal Adhesion Kinase through Extrinsic and Intrinsic Pathways in Human Melanoma Cells

1College of Natural Resources and Life Science, Dong-A University, Busan 604-714, Republic of Korea
2Medi-Farm Industrialization Research Center, Dong-A University, Busan 604-714, Republic of Korea
3Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, Sungkyunkwan University, Kyunggi-Do 440-746, Republic of Korea

Received 4 January 2013; Revised 29 March 2013; Accepted 7 April 2013

Academic Editor: Shrikant Anant

Copyright © 2013 Haw-Young Kwon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Triptolide (TPL) has been shown to inhibit cell proliferation and induce apoptosis in various human cancer cells; however, the precise mechanism of apoptosis induced by TPL in human melanoma cells has not yet been elucidated. In this study, we investigated the precise mechanism underlying cytocidal effects of TPL on human melanoma cells. Treatment of human melanoma cells with TPL significantly inhibited cell growth and induced apoptosis, as evidenced by flow cytometry and annexin V-fluorescein isothiocyanate analyses. TPL increased the levels of Fas and Fas-associated death domain (FADD) and induced cleavage of Bid by activation of caspase-8 and cytochrome c release from mitochondria to the cytosol, which resulted in activation of caspase-9 and caspase-3. Moreover, TPL-induced apoptosis in SK-MEL-2 cells was mediated through dephosphorylation of focal adhesion kinase (FAK) and its cleavage by caspase-8-mediated caspase-3 activation via upregulation of Fas expression. We also found that TPL mediated the dissociation of receptor-interacting protein (RIP) from FAK and enhanced the formation of RIP/Fas complex formation initiating cell death. In conclusion, our data firstly demonstrated that TPL induces apoptosis by both extrinsic and intrinsic apoptosis pathways in human melanoma cells and identified that RIP shuttles between Fas and FAK to mediate apoptosis.