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

Diacylglycerol (DAG)/phorbol ester-regulated protein kinase C isozymes have been widely linked to tumor promotion and the development of a metastatic phenotype. an oncogenic member of the 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 or other DAG-regulated and 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 duanyu1531ε expression in TGF-β-mesenchymally transformed NSCLC cells. PMA and AJH-836 (a DAG-mimetic that preferentially activates 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 duanyu1531ε enhances RhoA activity and stress fiber formation, a phenotype also observed in TGF-β-transformed cells. Our studies established a distinctive involvement of duanyu1531ε in epithelial and mesenchymal NSCLC cells, and identified a complex interplay between duanyu1531ε and small GTPases that contributes to regulation of NSCLC cell morphology and motile activity.

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