Protein kinase Cα mediates erlotinib resistance in lung cancer cells

Molecular Pharmacology
Mahlet B Abera, Marcelo G Kazanietz

Abstract

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 advanced 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 protein kinase C (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 transforming growth factor-β signaling. We found that H1650-M3 cells display remarkable PKCα upregulation and PKCδ downregulation. Notably, silencing PKCα from H1650-M3 cells using RNA interference caused a significant reduction in the expression of epithelial-to-mesenchymal transition (EMT) markers vimentin, Zeb2, Snail, and Twist. Moreover, pharmacological inhibition or PKCα RNA interference depletion and PKCδ restoring 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 resistan...Continue Reading

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Citations

Jan 21, 2016·Stem Cells International·Ninna Aggerholm-PedersenBoe Sandahl Sorensen
Jun 9, 2017·BMC Medical Genomics·Salem A El-AaragMahmoud ElHefnawi
Nov 25, 2016·JCI Insight·Mahlet B AberaBarrington G Burnett
Aug 25, 2020·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Jian JinRussell A Prough
Oct 6, 2020·Advances in Biological Regulation·Nilufar RahimovaMarcelo G Kazanietz
Dec 12, 2020·Advances in Biological Regulation·Adrian R Black, Jennifer D Black
Jun 3, 2021·International Journal of Molecular Sciences·Mohammad Mojtaba SadeghiYusuf A Hannun

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