Mitogenic and drug-resistance mediating effects of PKCalpha require RLIP76.
PKCalpha-activation is a key signaling event governing cell growth, stress-resistance, and drug-resistance. Our recent studies demonstrated that DOX-resistance mediating effects of PKCalpha 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 PKCalpha also require RLIP76. RLIP76-/- MEFs were resistant to PKCalpha-depletion mediated growth inhibition, as well as to the PKCalpha-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 PKCalpha-depletion and stimulation through PMA. These results show that RLIP76 is a necessary down-stream effector for PKCalpha-mediated mitogenesis.
Singhal
Sharad S
SS
Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019-0065, USA.
Yadav
Sushma
S
Singhal
Jyotsana
J
Awasthi
Yogesh C
YC
Awasthi
Sanjay
S
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D018288:Carcinoma, Small Cell; D002460:Cell Line; D049109:Cell Proliferation; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; D004317:Doxorubicin; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate