Mitogenic and drug-resistance mediating effects of PKCα require RLIP76

PKCα-activation is a key signaling event governing cell growth, stress-resistance, and drug-resistance. Our recent studies demonstrated that DOX-resistance mediating effects of PKCα require the presence of RLIP76, and their concerted action is sufficient to explain intrinsic DOX-resistance of NSCLC [S.S. Singhal, D. Wickramarachchi, J. Singhal, S. Yadav, Y.C. Awasthi, et al., Determinants of differential doxorubicin sensitivity between SCLC and NSCLC. FEBS Lett. 580 (2006) 2258–2264]. Present studies were carried out to further explore the suggestion from the previous studies that the mitogenic effects of PKCα also require RLIP76. RLIP76−/− MEFs were resistant to PKCα-depletion mediated growth inhibition, as well as to the PKCα-dependent mitogen, phorbol 12-myristate 13-acetate (PMA). Augmenting cellular levels of RLIP76 using purified recombinant RLIP76 increased growth rate in all cells, and restored the sensitivity of RLIP76−/− MEFs to both inhibition through PKCα-depletion and stimulation through PMA. These results show that RLIP76 is a necessary down-stream effector for PKCα-mediated mitogenesis.