Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways

Butyrate induces cytodifferentiation in many tumor cells of different origi n, suggesting that an as yet unidentified common mechanism inherent to mali gnant cells is the target of butyrate action. This study determined the rol e of different mitogen-activated protein (MAP) kinase signal transduction p athways in butyrate-induced erythroid differentiation of K562 human leukemi a cells. Using a panel of anti-ERK, JNK, and p38 phosphospecific antibodies , the study showed that phosphorylation of ERK and JNK is decreased followi ng treatment of cells with butyrate, whereas phosphorylation of p38 is incr eased. In contrast, a K562 subline defective in butyrate-mediated induction of erythroid differentiation did not reveal these changes in phosphorylati on patterns. Inhibition of ERK activity by UO126 induces erythroid differen tiation and acts synergistically with butyrate on hemoglobin synthesis and inhibition of cell proliferation, whereas inhibition of p38 activity by SB2 03580 completely abolished induction of hemoglobin expression by butyrate. Taken together, our data suggest a model in which butyrate induces erythroi d differentiation of K562 cells by inhibition of ERK and activation of p38 signal transduction pathways. (Blood, 2000;95:2391-2396) (C) 2000 by The Am erican Society of Hematology.