Targeting the Heat Shock Factor 1 by RNA Interference: A Potent Tool to Enhance Hyperthermochemotherapy Efficacy in Cervical Cancer

Abstract

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 heatinduced 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 siRNAmediated 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°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. (Cancer Res 2006; 66(15): 7678-85)

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

“…Thus, the combination of HT and HSF1-targeting may be an attractive option and worthy of further investigation. As expected, the inhibition of functions of HSF1 by using gene targeting or HSF1 inhibitors was shown to reduce the acquisition of thermoresistance (30)(31)(32)(33) and to sensitize tumors to HT-induced cell death (29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In the near future, targeting HSF1 (67,68) in combination with HT may come to be a promising approach for the treatment of cancer.…”

“…When HSF1 of cervical cancer cells was silenced by siRNA technology, the silencing in combination with hyperthermochemotherapy (treatment at 43˚C for 60 min plus cisplatin) markedly increased the level of apoptosis compared to hyperthermochemotherapy alone (38). In human melanoma cells, although HSF1 silencing did not sensitize to chemotherapy with dacarbazine, it significantly enhanced the sensitivity to this chemotherapy in combination with HT (42˚C, 60 min) (36).…”

“…The effects of inhibition of HSH1 on the hyperthermochemotherapy have been reported (36,38). When HSF1 of cervical cancer cells was silenced by siRNA technology, the silencing in combination with hyperthermochemotherapy (treatment at 43˚C for 60 min plus cisplatin) markedly increased the level of apoptosis compared to hyperthermochemotherapy alone (38).…”

“…(Table III). Of note, targeting of HSF1 has been suggested to enhance the sensitivity to HT under basic experimental conditions (29)(30)(31)(32)(33)(34)(35)(36)(37)(38). We recently showed that silencing HSF1 using small interfering RNA (siRNA) enhances the mild HT (42˚C, 90 min) and HT (44˚C, 90 min) sensitivity in human OSCC cells (37).…”

“…Elevation of HSF1 has been observed in several types of human tumor tissues (19)(20)(21)(22)(23)(24)(25)(26), and it has been shown to participate in the initiation, proliferation and maintenance of tumors (12,(25)(26)(27)(28)(29). Notably, both inhibition of the expression of HSF1 and the functional loss of HSF1 have been suggested to enhance the sensitivity to HT under basic experimental conditions (29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In the present review, the physiological and pathological roles of HSF1 in cancer cells are summarized, and the potential of HSF1 as a therapeutic target for HT therapy is discussed.…”