Carcinogenesis Advance Access published online on January 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi025
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1 Cancer Biology Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala-695 014, India
* To whom correspondence should be addressed. Multiple apoptotic stimuli induce conformational changes in Bax, a proapoptotic protein from the Bcl-2 family and its deficiency is a frequent cause of chemoresistance in colon adenocarcinomas. Curcumin, a dietary compound from turmeric, is known to induce apoptosis in a variety of cancer cells. To understand the role of Bax in curcumin-induced apoptosis we used HCT116 human colon cancer cells with one allele of Bax gene (Bax+/-) and Bax knockout HCT116 (Bax-/-) cells in which Bax gene is inactivated by homologous recombination. Cell viability decreased in a concentration-dependent manner in Bax+/- cells treated with curcumin (0-50 µM) whereas only minimal changes in viability were observed in Bax-/- cells upon curcumin treatment. In Bax-/- cells curcumin induced activation of caspases 9 and 3 was blocked and that of caspase 8 remained unaltered. Curcumin-induced release of cytochrome c, Smac and AIF was also blocked in Bax-/- cells and reintroduction of Bax, downregulation of the antiapoptotic protein Bcl-XL by anti sense DNA as well as overexpression of Smac highly sensitized the Bax-/- cells towards curcumin-induced apoptosis. There was no considerable difference in the percentage of apoptotic cells in Bak RNAi transfected Bax+/- or Bax-/- cells treated with curcumin when compared with their corresponding vector transfected cells treated with curcumin. The present study demonstrates the role of Bax but not Bak as a critical regulator of curcumin-induced apoptosis and implies the potential of targeting antiapoptotic proteins like Bcl-XL or over expression of proapoptotic proteins like Smac as interventional approaches to deal with Bax-deficient chemoresistant cancers for curcumin-based therapy. * This work was supported by, funding from the Kerala State Council for Science, Technology and the Environment (to D. K.), a grant from the Life Sciences Research Board, Defence Research Development Organization, Government of India (to D. K. and S. K.) and a Senior Research Fellowship (to R. R.) of the Council of Scientific and Industrial Research, Government of India.
Received May 17, 2004
Revised December 23, 2004
Accepted January 11, 2005
CANCER BIOLOGY
Human colon cancer cells lacking Bax resist curcumin-induced apoptosis and Bax requirement is dispensable with ectopic expression of Smac or downregulation of Bcl-XL*
Devarajan Karunagaran, E-mail: dkarunagaran{at}hotmail.com
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