IMPLICATION OF TYROSINE KINASES AND PROTEIN-KINASE-C IN DIMETHYL SULFOXIDE-INDUCED APOPTOSIS

We have previously shown that the chemical agent of myeloid differenti ation, dimethyl sulfoxide (DMSO), causes apoptosis in human leukemic U 937 cells (Chateau et al. Anal. Cell. Pathol. 1996;10:75-84). Activati on of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) led to inhibition of the DMSO-induced apoptosis, suggesting that PKC h elps regulate this mechanism by preventing cell death. However, specif ic inhibitors of PKC (bisin-dolylmaleimide, D sphingosine), neither tr iggered apoptosis themselves, nor affected the DMSO-induced apoptosis. Surprisingly, herbimycin A, a potent inhibitor of tyrosine kinases, d id not trigger apoptosis itself, but it did prevent DMSO-induced nucle ar fragmentation, whereas okadaic acid, an inhibitor of protein phosph atases, triggered apoptosis in U937 cells. These results suggest that DMSO-induced apoptosis requires the activation of an unidentified tyro sine kinase that is probably down-regulated by PKC activation.