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Depletion of Glutathione, Heat Shock Protein Synthesis, and the Development of Thermotolerance in Chinese Hamster Ovary Cells¹

Vanderbilt Center for Radiation Oncology [M. L. F.], Department of Biochemistry [M. J. M.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and Section of Cancer Biology [A. L.], Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University Medical Center, St. Louis, Missouri 63108

The synthesis of heat shock proteins (HSP) and the development of thermotolerance were studied in Chinese hamster ovary cells in order to determine whether depletion of intracellular glutathione (GSH) inhibited their expression. Cells were exposed to 100 µM diethylmaleate/50 µM buthionine sulfoximine which reduced GSH levels by 95% or more during the experimental time course. HSP synthesis was induced by incubation at 43°C for varying durations. Synthesis was independent of the diethylmaleate/buthionine sulfoximine treatment if mild heat shocks (e.g., 43°C for 15 min) were administered but was suppressed by such severe treatments as 45 or 60 min at 43°C which caused inhibition of non-heat shock protein synthesis. GSH depletion also resulted in inhibition of thermotolerance triggered by a 45-min, 43°C heat shock. This observation and a previous one, which showed that inhibition of protein synthesis by exposure to cycloheximide inhibited both HSP and tolerance (M. L. Freeman et al., Radiat. Res., 112: 564–574, 1987), indicate that glutathione is not involved in either the synthesis of HSP or the expression of tolerance but that GSH depletion can inhibit them indirectly via nonspecific inhibition of protein synthesis.

¹ This investigation was supported in part by USPHS Grants CA 38079, Ca 42591, ES 03272, and ES 00267.

² To whom requests for reprints should be addressed, at Vanderbilt Center for Radiation Oncology, E-1200, MCN, Vanderbilt University Hospital, Nashville, TN 37232.

Received 3/ 3/88. Revised 7/25/88. Revised 9/13/88. Accepted 9/19/88.

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