Carcinogenesis Advance Access originally published online on February 2, 2007
Carcinogenesis 2007 28(6):1277-1286; 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, TX 75703, USA
* To whom correspondence should be addressed at Department of Biochemistry and Molecular Biology, The University of Texas Health Center at Tyler, 11937 US Highway 271, Tyler, TX 75708-3154, USA. 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 pro-apoptotic 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 second mitochondria-derived activator of caspases (Smac)/direct inhibitor of apoptosis protein-binding protein with low isoelectric point], activation of caspase-9 and caspase-3 and ultimately apoptosis. Furthermore, MEFs derived from Bax and Bak double-knockout (DKO) 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 MEFs or single-knockout Bax–/– or Bak–/– MEFs. Interestingly, curcumin treatment also caused an increase in the protein level of apoptosis protease-activating factor-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 DKO 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 over-expression of Smac as interventional approaches to deal with Bax- and/or Bak-deficient chemoresistant cancers for curcumin-based therapy.
Abbreviations: Apaf-1, apoptosis protease-activating factor-1; DAPI, 4'-6-Diamidino-2-phenylindole; DIABLO, direct inhibitor of apoptosis protein-binding protein with low isoelectric point; DKO, double knockout; DMSO, dimethyl sulfoxide; FITC, fluorescein isothiocyanate; IAP, inhibitor of apoptosis protein; MEF, mouse embryonic fibroblast; OMM, outer mitochondrial membrane; PARP, poly-ADP ribose polymerase; PBS, phosphate-buffered saline; Smac, second mitochondria-derived activator of caspase; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand
Received October 20, 2006; revised January 10, 2007; accepted January 17, 2007.
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