Heat shock-induced accumulation of 70-kDa stress protein (HSP70) can protect ATP-depleted tumor cells from necrosis.
The phenomenon of cell resistance to prolonged energy deprivation after mild thermal stress was studied in vitro. Murine P3O1 myeloma and Ehrlich ascites carcinoma cells were treated with rotenone (an inhibitor of respiration) in glucose-free medium to block ATP generation. ATP rapidly decreased in these cells to 3-6% of the initial level that resulted in powerful aggregation of cytoskeletal proteins, blebbing, and necrotic death of 60-70% cells within 2 h. Prior heat shock (43 degrees C for 10 min) with a subsequent 3-h recovery in a rich medium considerably suppressed the rotenone-induced actin aggregation and rate of necrosis in the energy-deprived cells without effecting the ATP drop in them. Using [14C]leucine labeling, gel electrophoresis, and fluorography, stimulation of the heat-shock protein (HSP) synthesis and total suppression of any other translation were revealed in the cells during recovery after the heat pretreatment. Significantly elevated levels of HSP70 but not HSP90 and HSP27 were found by means of immunoblotting in both cell cultures rendered resistant to necrosis under ATP-depleting conditions. Inhibition of the thermo-induced HSP synthesis by cycloheximide fully prevented development of the tolerance to energy deprivation. A novel function of HSP70 consisting of protection of ATP-deprived cells from "lethal" aggregation of cytoskeletal proteins is suggested.
Kabakov
A E
AE
Medical Radiology Research Center, Russian Academy of Medical Sciences, Obninsk.
Gabai
V L
VL
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000502:physiology*; D006358:Hot Temperature; D007511:Ischemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D009336:Necrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018840:HSP70 Heat-Shock Proteins; D011500:Protein Synthesis Inhibitors; D012402:Rotenone; D000255:Adenosine Triphosphate; D003513:Cycloheximide