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Distinctive requirement of PKCε in the control of Rho GTPases in epithelial and mesenchymally transformed lung cancer cells

Oncogene volume 38, pages 5396–5412 (2019)Cite this article

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Abstract

Diacylglycerol (DAG)/phorbol ester-regulated protein kinase C (PKC) isozymes have been widely linked to tumor promotion and the development of a metastatic phenotype. PKCε, an oncogenic member of the PKC family, is abnormally overexpressed in lung cancer and other cancer types. This kinase plays significant roles in proliferation, survival, and migration; however, its role in epithelial-to-mesenchymal transition (EMT) has been scarcely studied. Silencing experiments in non-small lung cancer (NSCLC) cells revealed that PKCε or other DAG-regulated PKCs (PKCα and PKCδ) were dispensable for the acquisition of a mesenchymal phenotype induced by transforming growth factor beta (TGF-β). Unexpectedly, we found a nearly complete down-regulation of PKCε expression in TGF-β-mesenchymally transformed NSCLC cells. PMA and AJH-836 (a DAG-mimetic that preferentially activates PKCε) promote ruffle formation in NSCLC cells via Rac1, however they fail to induce these morphological changes in TGF-β-mesenchymally transformed cells despite their elevated Rac1 activity. Several Rac guanine nucleotide exchange-factors (Rac-GEFs) were also up-regulated in TGF-β-treated NSCLC cells, including Trio and Tiam2, which were required for cell motility. Lastly, we found that silencing or inhibiting PKCε enhances RhoA activity and stress fiber formation, a phenotype also observed in TGF-β-transformed cells. Our studies established a distinctive involvement of PKCε in epithelial and mesenchymal NSCLC cells, and identified a complex interplay between PKCε and small GTPases that contributes to regulation of NSCLC cell morphology and motile activity.

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Acknowledgements

This work was supported by grant R01-ES026023 and R01-ES026023-S1 from the National Institutes of Health to M.G.K.

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  1. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104-6160, USA

    Victoria Casado-Medrano, Laura Barrio-Real, Anita Wang, Mariana Cooke, Cynthia Lopez-Haber & Marcelo G. Kazanietz

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Casado-Medrano, V., Barrio-Real, L., Wang, A. et al. Distinctive requirement of PKCε in the control of Rho GTPases in epithelial and mesenchymally transformed lung cancer cells. Oncogene 38, 5396–5412 (2019). https://doi.org/10.1038/s41388-019-0796-4

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