Journal Article

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

Ramachandran Rashmi, Santhosh Kumar and Devarajan Karunagaran

in Carcinogenesis

Volume 26, issue 4, pages 713-723
Published in print April 2005 | ISSN: 0143-3334
Published online April 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi025
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

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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, Second mitochondria derived activator of caspase (Smac) and apoptosis inducing factor (AIF) was also blocked in Bax−/− cells and reintroduction of Bax, downregulation of the antiapoptotic protein Bcl-XL by antisense DNA as well as the overexpression of Smac, highly sensitized the Bax−/− cells toward 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 overexpression of proapoptotic proteins like Smac as interventional approaches to deal with Bax-deficient chemoresistant cancers for curcumin-based therapy.

Keywords: Apaf-1, apoptosis protease activating factor-1; AIF, apoptosis inducing factor; AFC, 7-amino-4-trifluoromethyl coumarin; DAPI, 4,6-diamidino-2-phenylindole; GFP, green fluorescent protein; IAP, inhibitor of apoptosis proteins; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PARP, poly (ADP) ribose polymerase; PBS, phosphate buffered saline; Smac, second mitochondria derived activator of caspase; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand

Journal Article.  7504 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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