Carcinogenesis Advance Access published online on February 2, 2007
Carcinogenesis, doi:10.1093/carcin/bgm024
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Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric, Curcuma longa
Department of Biochemistry, University of Texas Health Center at Tyler, Tyler, Texas, USA 75703
Correspondence: Rakesh K. Srivastava, Department of Biochemistry and Molecular Biology, The University of Texas Health Center at Tyler, 11937 US Highway 271, Tyler, Texas 75708-3154. Tel: 903-877-7559. Fax: 903-877-5320. Email: rakesh.srivastava{at}uthct.edu
Curcumin, an active ingredient of turmeric (Curcuma longa), inhibits proliferation and induces apoptosis in cancer cells, but the sequence of events leading to cell death is poorly defined. The objective of this study was to examine the molecular mechanisms by which multidomain proapoptotic Bcl-2 family members Bax and Bak regulate curcumin-induced apoptosis using mouse embryonic fibroblasts (MEFs) deficient in Bax, Bak or both genes. Curcumin treatment resulted an increase in the protein levels of both Bax and Bak, and mitochondrial translocation and activation of Bax in MEFs to trigger drop in mitochondrial membrane potential, cytosolic release of apoptogenic molecules (cytochrome c and Smac/DIABLO), activation of caspase-9 and caspase-3, and ultimately apoptosis. Furthermore, MEFs derived from Bax and Bak double knockout mice exhibited even greater protection against curcumin-induced release of cytochrome c and Smac, activation of caspase-3 and caspase-9, and induction of apoptosis compared with wild-type, or single knockout Bax-/- or Bak-/- MEFs. Interestingly, curcumin treatment also caused an increase in the protein level of Apaf-1 in wild-type MEFs. Smac N7 peptide enhanced curcumin-induced apoptosis, whereas Smac siRNA inhibited the effects of curcumin on apoptosis. Mature form of Smac sensitized Bax and Bak double knockout MEFs to undergo apoptosis by acting downstream of mitochondria. The present study demonstrates the role of Bax and Bak as a critical regulator of curcumin-induced apoptosis and overexpression of Smac as interventional approaches to deal with Bax- and/or Bak-deficient chemo-resistant cancers for curcumin-based therapy.
Key Words: Bax • Bak • apoptosis • prostate cancer • curcumin • mitochondria • caspase
Received October 20, 2006; revised January 10, 2007; accepted January 17, 2007.
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