IFN-gamma Down-regulates Hsp27 and Enhances Hyperthermia-induced Tumor Cell Death in Vitro and Tumor Suppression in Vivo

Hyperthermia is used as one of the treatment modalities for various types of cancer, but the acquisition of thermotolerance in cancer cells, through the induction of heat shock proteins (Hsps), renders hyperthermia less effective. Among the Hsp family members, Hsp27 is frequently associated with thermotolerance and chemoresistance. Thus, down-regulation of Hsp27 expression during hyperthermic or chemotherapeutic applications is a promising approach to efficient tumor treatment. In the present study, we found that the cytokine interferon-gamma (IFN-gamma) suppresses the basal, the heat shock-induced and the cisplatin-induced expression of Hsp27 in HSC-2 (oral squamous carcinoma) and A549 (lung cancer) cells but not in 16HBE14o- (normal bronchial epithelial cells). Neither IFN-alpha nor IFN-beta affected Hsp27 expression, suggesting the specificity of IFN-gamma. We also demonstrate here that IFN-gamma suppresses Hsp27 basal transcription and promoter activity, and this is mediated specifically through one of the two Sp1 sites in the proximal region of the Hsp27 promoter. More importantly, pre-treatment of cells with IFN-gamma enhanced the induction of cell death by hyperthermia and cisplatin treatments in the tumor cell lines, HSC-2 and A549, but has no effect in 16HBE14o-, indicating a tumor cell-specific effect of IFN-gamma. Furthermore, the combination treatment of hyperthermia and IFN-gamma suppressed tumor growth in vivo more effectively than hyperthermia treatment alone. Together, our findings propose that IFN-gamma could be a useful potentiator of hyperthermia and cisplatin in cancer therapy.