Oncogenic ras results in increased cell kill due to defective thermoprotection in lung cancer cells

Background. The survival response of normal cells to heat stress is an upre gulation of heat shock proteins and ras protein activation. We hypothesized that in lung cancer cells the presence of oncogenic ms interferes with the rmoprotective mechanisms resulting in cell death. Methods. An equal number of lung tissue culture cells (normal and cancerous ) were subjected to either heat stress and then recovery (43 degrees C for 180 minutes, 37 degrees C for 180 minutes) or recovery alone (37 degrees C for 360 minutes). End points were surviving number of cells, cell-death tim e course, heat shock protein (HSP70, HSC70, HSP27) expression before and af ter heat stress, and time course for HSP70 expression during heat stress an d recovery. Heated cells were compared with unheated control cells, then th is difference was compared between cell types. Results. Heat stress in normal cells caused an 8% decrease in cell number v ersus a 78% +/- 5% decrease in cancer cells (p < 0.05). In normal cells, he at stress caused a 4.4-fold increase in HSP70, no change in HSC70, and a 1. 7-fold increase in HSP27. In contrast, cancer cells initially contained sig nificantly less HSP70 (p < 0.05), and there was a 27-fold increase in HSP70 and a 2-fold increase in HSC70 with no HSP27 detected (comparison signific ant, p < 0.05). HSP70 time course in normal cells showed that HSP70 increas ed 100-fold, reaching a vertex at 2 hours and remaining elevated for 24 hou rs; in cancer cells, HSP70 maximum expression (100-fold) peaked at 5 hours, then decreased to slightly elevated at 24 hours. Conclusions. Cancer cells with oncogenic ras have defective thermoprotectiv e mechanism(s) causing increased in vitro cell death, which provides an opp ortunity for thermal treatment of lung cancer. (C) 2000 by The Society of T horacic Surgeons.