Upregulation of heat shock protein 27 confers resistance to actinomycin D-induced apoptosis in cancer cells

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Abstract

Actinomycin D (Act D) is a general transcriptional inhibitor that is approved for the treatment of sarcomas, and Wilms, germ cell and trophoblastic tumors. Little is known about the molecular mechanisms that dictate the sensitivity of cancer cells to Act D. In this study, we investigated the effects of Act D on heat shock proteins (HSPs) and the expression and roles of HSP27 in Act D-induced cancer cell apoptosis. We show that Act D upregulates HSP27 and HSP70 expression in cancer cells, whereas it inhibits HSP90 expression. The upregulation of HSP27 by Act D is not attributable to changes in HSP27 transcription or HSP27 synthesis. HSP27 knockdown leads to an increase in Act D-induced caspase 3 and caspase 7 cleavage, and sensitizes rhabdosarcoma cells and breast cancer cells to Act D-induced apoptosis. We conclude that upregulation of HSP27 represents an adaptive response that compromises the anticancer activity of Act D.

The anticancer agent actinomycin D (Act D) up-regulates heat shock protein 27 (HSP27) through preventing its degradation. HSP27 knockdown leads to an increase in actinomycin D-induced caspase 3 and caspase 7 cleavage, and sensitizes Act D-induced apoptosis in rhabdosarcoma cells and breast cancer cells. Upregulation of HSP27 represents an adaptive response that compromises the anticancer activity of Act D.

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