Carcinogenesis Advance Access published online on November 6, 2003
Carcinogenesis, doi:10.1093/carcin/bgh001
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Division of Cancer Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala-695014, India
* Corresponding author. E-mail: dkarunagaran{at}hotmail.com.
Received 9 July 2003
; revised 30 August 2003
; accepted 14 October 2003
We have shown earlier that heat shock renders human colon cancer cells resistant to curcumin-induced apoptosis, but contribution of individual heat shock proteins (hsps) to this resistance has not been tested. High expression of hsp27 and hsp70, in breast, endometrial, or gastric cancers has been associated with metastasis, poor prognosis and resistance to chemo- or radio-therapy. In this study, SW480 cells were transfected with hsp70cDNA either in sense or antisense orientation and stable clones were selected and tested for their sensitivity to curcumin. The cells were protected from curcumin-induced cell death by hsp70 while the cells harboring antisense hsp70 (Ashsp70) were highly sensitive to curcumin. Curcumin-induced nuclear condensation was less in hsp70 but more in Ashsp70 cells when compared with control vector-transfected cells. Loss of mitochondrial transmembrane potential induced by curcumin was accelerated further by the antisense hsp70 expression and hsp70 restored it partly. Ashsp70 cells released more of cytochrome c, AIF and Smac from mitochondria upon curcumin treatment than the control cells but hsp70 partly prevented the release of AIF but not others. Activation of caspases 3 and 9 induced by curcumin was also inhibited by hsp70 whereas more activation could be seen in Ashsp70 cells although caspase 8 activation was unaffected by changes in hsp70 expression. Curcumin-induced cleavage of PARP and DFF45 was inhibited by hsp70 but enhanced in Ashsp70 cells. The present study demonstrates the potential of hsp70 in protecting SW480 cells from curcumin-induced apoptosis and highlights that silencing the expression of hsp70 with its antisense is an effective approach to augment curcumin-based therapy in cancers that are resistant due to hsp70 expression.
Hsp70, apoptosis, curcumin, AIF, Smac, cytochrome c, antisense therapy
Ectopic expression of hsp70 confers resistance, and silencing its expression sensitizes human colon cancer cells to curcumin-induced apoptosis
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