Carcinoma of the uterine cervix is one of the highest causes of mortality in female
cancer patients worldwide, and improved treatment options for this type of
malignancy are highly needed.
Local hyperthermia has been successfully used in combination with systemic administration of
cisplatin-based
chemotherapy in phase I/II clinical studies. Heat-induced expression of cytoprotective and antiapoptotic
heat shock proteins (HSP) is a known complication of
hyperthermia, resulting in thermotolerance and chemoresistance and hindering the efficacy of the combination
therapy.
Heat shock transcription factor 1 (HSF1) is the master regulator of heat-induced HSP expression. In the present report, we used
small interfering RNA (
siRNA) to silence HSF1 and to examine the effect of HSF1 loss of function on the response to
hyperthermia and
cisplatin-based
chemotherapy in HeLa cervical
carcinoma. We have identified the 322-nucleotide to 340-nucleotide HSF1 sequence as an ideal target for
siRNA-mediated HSF1 silencing, have created a pSUPER-HSF1 vector able to potently suppress the HSF1 gene, and have generated for the first time human
cancer cell lines with stable loss of HSF1 function. We report that, although it surprisingly does not affect
cancer cell sensitivity to
cisplatin or elevated temperatures up to 43 degrees C when administered separately, loss of HSF1 function causes a dramatic increase in sensitivity to hyperthermochemotherapy, leading to massive (>95%) apoptosis of
cancer cells. These findings indicate that disruption of HSF1-induced cytoprotection during hyperthermochemotherapy may represent a powerful strategy to selectively amplify the damage in
cancer cells and identify HSF1 as a promising therapeutic target in cervical
carcinoma.