Mitogenic and drug-resistance mediating effects of PKCalpha require RLIP76

Biochem Biophys Res Commun. 2006 Sep 22;348(2):722-7. doi: 10.1016/j.bbrc.2006.07.118. Epub 2006 Jul 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Small Cell
  • Cell Line
  • Cell Proliferation
  • Doxorubicin / therapeutic use
  • Drug Resistance, Neoplasm
  • GTPase-Activating Proteins / deficiency
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Mice
  • Protein Kinase C-alpha / metabolism*
  • Signal Transduction
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Cells, Cultured

Substances

  • ATP-Binding Cassette Transporters
  • GTPase-Activating Proteins
  • RALBP1 protein, human
  • Doxorubicin
  • Protein Kinase C-alpha
  • Tetradecanoylphorbol Acetate