Phorbol ester inhibits DNA damage-induced apoptosis in U937 cells through activation of protein kinase C

The effects of phorbol 12-myristate 13-acetate (PMA) on DNA damage-induced apoptosis were examined in promyelocytic leukemia cells, U937, in compariso n with other differentiation-inducing agents to clarify the role of protein kinase C (PKC) vis-a-vis cellular differentiation in apoptosis. The apopto sis of U937 cells was observed at as early as 1-1.5 h following UV irradiat ion, with most cells being in apoptotic state at 3 h. Pretreatment with PMA for as short as 5 min was sufficient to inhibit apoptosis induced by UV ir radiation, whereas apparent changes in cell cycle distributions and express ion of differentiation markers by PMA were not observed until 12 h and 48 h , respectively. The inhibition of apoptosis by PMA was completely abolished by the pretreatment with calphostin C, a PKC inhibitor, and 4 alpha-phorbo r 12,13-didecanoate, which is unable to activate PKC, did not protect U937 cells against apoptosis induced by UV irradiation. Other differentiation in ducers, such as cyclic AMP and active vitamin D-3, did not affect the UV-in duced apoptosis of U937 cells. Taken together, it was suggested that PMA in hibits DNA damage-induced apoptosis through the activation of PKC rather th an as a result of differentiation of U937 cells.