International journal of radiation oncology, biology, physics · 1996
Effect of adenosine 3':5'-cyclic monophosphate and inhibition of protein kinase A on heat sensitivity in H35 hepatoma cells.
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van Rijn J, van den Berg J
Аннотация
PURPOSE: To investigate the role of the cyclic adenosine 3':5'-monophosphate (AMP) signal transductions pathway in heat-induced cell death and the development of thermotolerance.
METHODS AND MATERIALS: Reuber H35 rat hepatoma cells were heated after preincubation with various compounds known to modulate the cyclic AMP signal transduction pathway. Cell survival was determined by colony-forming ability.
RESULTS: Preincubation of H35 cells with forskolin, a stimulator of adenylate cyclase, in combination with IBMX (3-isobutyl-1-methylxanthine), an inhibitor of cyclic AMP phosphodiesterase, results in thermosensitization. Similar results are obtained with various cyclic AMP analogs. Maximum thermosensitization occurs with 0.5 mM dibutyryl cyclic AMP (DBcAMP) after a preincubation period of 5 h and heating in the presence of the drug. The same relative degree of thermosensitization is found with 8-Cl-cAMP, but at a 10-fold lower concentration. Thermosensitization by DBcAMP is prevented by H89, a specific inhibitor of cyclic AMP-dependent protein kinase (PKA). Without additional cyclic AMP-inducing factors, H89 induces thermoprotection. None of the drug treatments are cytotoxic at 37 degrees C. DBcAMP does not affect the development of heat-induced thermotolerance but it reduces its expression to an extent similarly found in the observed thermosensitization in nonthermotolerant cells.
CONCLUSION: The results strongly indicate that the cyclic AMP signal transduction pathway is involved in the process of heat-induced cell death. DBcAMP reduces the expression of thermotolerance, but does not affect its induction.
METHODS AND MATERIALS: Reuber H35 rat hepatoma cells were heated after preincubation with various compounds known to modulate the cyclic AMP signal transduction pathway. Cell survival was determined by colony-forming ability.
RESULTS: Preincubation of H35 cells with forskolin, a stimulator of adenylate cyclase, in combination with IBMX (3-isobutyl-1-methylxanthine), an inhibitor of cyclic AMP phosphodiesterase, results in thermosensitization. Similar results are obtained with various cyclic AMP analogs. Maximum thermosensitization occurs with 0.5 mM dibutyryl cyclic AMP (DBcAMP) after a preincubation period of 5 h and heating in the presence of the drug. The same relative degree of thermosensitization is found with 8-Cl-cAMP, but at a 10-fold lower concentration. Thermosensitization by DBcAMP is prevented by H89, a specific inhibitor of cyclic AMP-dependent protein kinase (PKA). Without additional cyclic AMP-inducing factors, H89 induces thermoprotection. None of the drug treatments are cytotoxic at 37 degrees C. DBcAMP does not affect the development of heat-induced thermotolerance but it reduces its expression to an extent similarly found in the observed thermosensitization in nonthermotolerant cells.
CONCLUSION: The results strongly indicate that the cyclic AMP signal transduction pathway is involved in the process of heat-induced cell death. DBcAMP reduces the expression of thermotolerance, but does not affect its induction.