Modulation of Heat-Shock Protein 70 (HSP70) Gene Expression by Sodium Butyrate in U-937 Promonocytic Cells: Relationships with Differentiation and Apoptosis

Abstract

The administration of sodium butyrate at 0.75 mMinduced the functional differentiation of U-937 human promonocytic leukemia cells with negligible cell mortality. However, the drug rapidly caused cell death with characteristics of apoptosis when used at concentrations of 5 mMand above. In addition, butyrate stimulated the expression of the stress-responsive heat-shock protein 70 (HSP70) gene when applied at both differentiation-inducing and apoptosis-inducing concentrations. The induction ofHSP70by butyrate was inhibited by the simultaneous addition of cAMP-increasing agents (dibutyryl cAMP or the combination of forskolin plus theophylline). However, these agents did not prevent differentiation and only partially reduced apoptosis. Moreover, the DNA topoisomerase II inhibitor etoposide, which provoked U-937 cell differentiation and apoptosis with the same or greater efficiency than butyrate, failed to stimulateHSP70expression. Finally, it was observed that cAMP-increasing agents also abrogated the induction ofHSP70and reduced the apoptosis caused by cadmium chloride, a typical inducer of the stress response. Taken together, these results indicate thatHSP70expression is not required for differentiation of promonocytic cells, as earlier proposed, and that butyrate probably triggers the stress response in these cells.