A Priming Heat Treatment Can Induce the Development of Heat- and Radio-resistance via HSPs, Regardless of p53-gene Status

Abstract

It has been suggested that inducible heat shock proteins (HSPs) may function in multiple roles in cytoprotection. However, recent reports have shown that nitric oxide (NO) radicals are an initiator of heat- and radio-resistance, and act through the activation of the human homolog of MDM2 (HDM2), the depression of p53 accumulation, and the induction of NO synthase (iNOS, or alternatively, NOS2) which is observed following a priming irradiation. The aim of this work was to acquire additional information on the roles of p53, HDM2, iNOS, NO radicals, and HSPs on the development of heat- and radio-resistance as following a priming heat treatment. Wild-type (wt) p53 and mutated (m) p53 cells were used. These cells were derived from the H1299 human lung cancer cell line in which p53 is deleted. Cellular sensitivities were determined with a colony-forming assay. In both pre-heated wtp53 cells and in pre-heated mp53 cells, the induction of heat- and radio-resistance was observed in the absence of KNK437 (an inhibitor of HSPs), and in the presence of RITA (an inhibitor of p53-HDM2 interactions), aminoguanidine (an iNOS inhibitor) or c-PTIO (an NO radical scavenger). These findings suggest that following a priming heat treatment, HSPs contribute to heat- and radio-resistance.