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 expr ession, Although there was a variability in the sensitivity of pancrea tic carcinoma cell lines to heat, enTNF and HSP72 expression as well a s MnSOD activity correlated positively with heat resistance. When MIAP aCa-2 pancreatic carcinoma cells, which had the lowest enTNF expressio n and highest heat sensitivity, were transfected with a nonsecretory-h uman TNF gene (pTNF Delta pro), intracellular manganous superoxide dis mutase (MnSOD) activity, HSP72 expression, and heat resistance were si gnificantly increased. Furthermore, in these cells, enTNF expression c orrelated with the binding activity of heat shock factor 1 (HSF 1) to an oligonucleotide containing the human heat shock element. These resu lts indicate that enTNF participates in the intrinsic resistance again st heat via induction of MnSOD. enhances HSF1-binding activity, and au gments of HSP72 expression. Therefore, inhibition of enTNF expression in pancreatic carcinoma cells would improve the efficacy of hypertherm ia for pancreatic carcinoma.