No abstract

Toll-like receptor 3 (TLR3) has gained recognition as a novel molecular target for cancer therapy because TLR3 activation by its synthetic ligand poly I:C directly causes tumor cell death. Recently, we reported that tumor suppressor p53 increases the expression of TLR3 in several tumor cell lines. Another study also showed that interferon-a (IFN-a) up-regulates TLR3 expression. We thus hypothesized that various anticancer drugs such as p53-activating reagents and IFNs may potentiate poly I:C-induced tumor cell death through the up-regulation of TLR3 expression. Here, we screened several anticancer drugs that, together with poly I:C, effectively cause tumor cell death in colon carcinoma HCT116 cells. We found that the DNA-damaging reagent 5-fluorouracil (5-FU) increased TLR3 mRNA expression and potentiated poly I:C-induced apoptosis in HCT116 p53 + ⁄ + cells but had only minimal effect in p53indicating a p53-dependent pathway. On the other hand, IFN-a increased poly I:C-induced apoptosis and the TLR3 mRNA level in HCT116 p53 + ⁄ + and p53 ) ⁄ ) cell lines. Furthermore, the combination of poly I:C, 5-FU and IFN-a induced the highest apoptosis in HCT116 p53 + ⁄ + and p53 ) ⁄ ) cells. Taken together, these data suggest that the anticancer drugs increased TLR3 expression and subsequently potentiated poly I:C-induced apoptosis likely via p53-dependent and -independent pathways. Considering that the p53 status in malignant cells is heterogeneous, this combination approach may provide a highly effective tumor therapy.

Abstract. 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-γ) 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-α nor IFN-ß affected Hsp27 expression, suggesting the specificity of IFN-γ. We also demonstrate here that IFN-γ 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, pretreatment of cells with IFN-γ 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-γ. Furthermore, the combination treatment of hyperthermia and IFN-γ suppressed tumor growth in vivo more effectively than hyperthermia treatment alone. Together, our findings propose that IFN-γ could be a useful potentiator of hyperthermia and cisplatin in cancer therapy.

Abstract. 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-γ) 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-α nor IFN-ß affected Hsp27 expression, suggesting the specificity of IFN-γ. We also demonstrate here that IFN-γ 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, pretreatment of cells with IFN-γ 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-γ. Furthermore, the combination treatment of hyperthermia and IFN-γ suppressed tumor growth in vivo more effectively than hyperthermia treatment alone. Together, our findings propose that IFN-γ could be a useful potentiator of hyperthermia and cisplatin in cancer therapy.

No abstract