Activation of extracellular signal-regulated kinase and c-Jun-NH2-terminalkinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells

RRR-alpha -tocopherol succinate (vitamin E succinate, VES) is a potent, sel ective apoptotic agent for cancer cells but not normal cells. VES has been shown to inhibit the growth of a wide variety of tumor cells in cell cultur e and animal models. Studies addressing mechanisms of action of VES-induced apoptosis have identified transforming growth factor-beta, Fas/CD95-APO-1, and mitogen-activated protein kinase (MAPK) signaling pathway involvement. Here we show that MAPKs, the extracellular signal-regulated kinases (ERK), and the stress-activated protein kinases, c-Jun NH2-terminal kinases (JNK) , but not p38, are critical mediators in VES-induced apoptosis of human bre ast cancer MDA-MB-435 cells. VES activates ERK1/2 and JNK both in level and duration of kinase activity. Expression of dominant negative mutants of ER K1, MAPK/ERK activator-1, or JNK1 but not p38 blocked phosphorylation of th e substrate glutathione S-transferase-c-Jun and inhibited VES-induced apopt osis. Increased phosphorylation and transactivation activity of nuclear tra nscription factors c-Jun, ATF-2, and Elk-1 are observed after VES treatment s; however, only c-Jun and ATF-2 appear to be involved in VES-induced apopt osis based on antisense blockage experiments. Collectively, these results i mply a critical role for ERK1 and JNK1 but not p38 in VES-induced apoptosis of human MDA-MB-435 breast cancer cells.