HYPERTHERMIA MODULATES CISPLATIN SENSITIVITY

SOTTILE ML; CUELLO-CARRIÓN FD; VARGAS-ROIG LM; CIOCCA DR; NADIN SB

Porto Alegre

Workshop; IX Cell Stress Society International Workshop on the Molecular Biology of Stress Responses; 2012

Cell Stress Society International

Introduction. A mild hyperthermia (39-42°C) induces the expression of heat shock proteins (HSPs). HSPB1 (HSP27) and HSPA1A (HSP72) participate in cell proliferation and survival; they were also implicated in resistance to antineoplasic drugs, ie cisplatin (cPt).  The cytotoxicity of cPt is mediated by DNA-crosslinks formation; which are recognized by components of the Mismatch Repair system (MMR). Defects of MMR proteins, such as hMLH1 and hMSH2, have been related to cPt resistance. Recently, we have reported that hyperthermia induced the nuclear accumulation of HSPB1 and HSPA1A and affected the subcellular localization of hMLH1 and hMSH2 in MMR proficient colon cancer cells. However, the implications of HSPs on cisplatin DNA damage/repair mediated by MMR system have not been determined in MMR deficient/proficient tumor cell lines. HCT116 and HCT116+ch2 (MMR deficient) and HCT116+ch3 (MMR proficient) were exposed to: 1- cPt, 10 µM (1 h) and 2- HS+cPt, 10 µM (1 h) 24 h after HS (42°C, 1 h). Cells were collected after treatments at times: 0 (immediately after cPt), 4 and 24 h after cPt. Gene expressions were evaluated using qRT-PCR, DNA damage by alkaline comet assay, senescence by cytochemical detection of SA-âgal activity and apoptosis by TUNEL. Results. cPt reduced the expression of HSPB1 in HCT116+ch3 cells (P