RT Journal Article
SR Electronic
T1 Protein Kinase C Alpha Mediates Erlotinib Resistance in Lung Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.097725
DO 10.1124/mol.115.097725
A1 Mahlet B Abera
A1 Marcelo G. Kazanietz
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/02/27/mol.115.097725.abstract
AB Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC). EGFR tyrosine-kinase inhibitors (TKIs) are given as a primary therapy for patients with EGFR activating mutations; however, the majority of these tumors relapse and patients eventually develop resistance to TKIs. To address a potential role of PKC isozymes in the resistance to TKIs, we used the isogenic NSCLC H1650 cell line and its erlotinib-resistant derivative H1650-M3, a cell line that displays a mesenchymal-like morphology driven by TGF-β signaling (PNAS 107:15535-15540, 2010). We found that H1650-M3 cells display remarkable PKCα up-regulation and PKCδ down-regulation. Notably, silencing PKCα from H1650-M3 cells using RNAi caused a significant reduction in the expression of EMT markers vimentin, Zeb2, Snail and Twist. Moreover, pharmacological inhibition or PKCα RNAi depletion sensitized H1650-M3 cells to erlotinib. Whereas ectopic overexpression of PKCα in parental H1650 cells was not sufficient to alter the expression of EMT genes or to confer resistance to erlotinib, it caused down-regulation of PKCδ expression. Restoring PKCδ levels in H1650-M3 cells to those observed in the parental cells also sensitized cells to erlotinib. Finally, mechanistic studies revealed that PKCα up-regulation in H1650-M3 cells is driven by TGF-β. Our results identified important roles for specific PKC isozymes in erlotinib resistance and EMT in lung cancer cells, and highlight PKCα as a potential target for lung cancer treatment.