Endogenous tumor necrosis factor functions as a resistant factor against hyperthermic cytotoxicity in pancreatic carcinoma cells via enhancement of the heat shock element-binding activity of heat shock factor 1

To elucidate the relationship between two distinct resistant factors, endogenous tumor necrosis factor (enTNF) and heat shock proteins (HSPs), against hyperthermia, we assessed whether enTNF enhances HSP72 expression, Although there was a variability in the sensitivity of pancreatic carcinoma cell lines to heat, enTNF and HSP72 expression as well as MnSOD activity correlated positively with heat resistance. When MIAPaCa-2 pancreatic carcinoma cells, which had the lowest enTNF expression and highest heat sensitivity, were transfected with a nonsecretory-human TNF gene (pTNF Delta pro), intracellular manganous superoxide dismutase (MnSOD) activity, HSP72 expression, and heat resistance were significantly increased. Furthermore, in these cells, enTNF expression correlated with the binding activity of heat shock factor 1 (HSF 1) to an oligonucleotide containing the human heat shock element. These results indicate that enTNF participates in the intrinsic resistance against heat via induction of MnSOD. enhances HSF1-binding activity, and augments of HSP72 expression. Therefore, inhibition of enTNF expression in pancreatic carcinoma cells would improve the efficacy of hyperthermia for pancreatic carcinoma.