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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.
Carcinogenesis. 2005 Apr; 26(4):713-23.C

Abstract

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 microM) 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 chemo-resistant cancers for curcumin-based therapy.

Authors+Show Affiliations

Cancer Biology Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala 695 014, India.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15661804

Citation

Rashmi, Ramachandran, et al. "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." Carcinogenesis, vol. 26, no. 4, 2005, pp. 713-23.
Rashmi R, Kumar S, Karunagaran D. 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. Carcinogenesis. 2005;26(4):713-23.
Rashmi, R., Kumar, S., & Karunagaran, D. (2005). 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. Carcinogenesis, 26(4), 713-23.
Rashmi R, Kumar S, Karunagaran D. 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. Carcinogenesis. 2005;26(4):713-23. PubMed PMID: 15661804.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Rashmi,Ramachandran, AU - Kumar,Santhosh, AU - Karunagaran,Devarajan, Y1 - 2005/01/20/ PY - 2005/1/22/pubmed PY - 2005/5/4/medline PY - 2005/1/22/entrez SP - 713 EP - 23 JF - Carcinogenesis JO - Carcinogenesis VL - 26 IS - 4 N2 - 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 microM) 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 chemo-resistant cancers for curcumin-based therapy. SN - 0143-3334 UR - https://www.unboundmedicine.com/medline/citation/15661804/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_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgi025 DB - PRIME DP - Unbound Medicine ER -