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

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. PKC?, 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 PKC? or other DAG-regulated PKCs (PKC? and PKC?) were dispensable for the acquisition of a mesenchymal phenotype induced by transforming growth factor beta (TGF-?). Unexpectedly, we found a nearly complete down-regulation of PKC? expression in TGF-?-mesenchymally transformed NSCLC cells. PMA and AJH-836 (a DAG-mimetic that preferentially activates PKC?) promote ruffle formation in NSCLC cells via Rac1, however they fail to induce these morphological changes in TGF-?-mesenchymally transformed cells despite their elevated Rac1 activity. Several Rac guanine nucleotide exchange-factors (Rac-GEFs) were also up-regulated in TGF-?-treated NSCLC cells, including Trio and Tiam2, which were required for cell motility. Lastly, we found that silencing or inhibiting PKC? enhances RhoA activity and stress fiber formation, a phenotype also observed in TGF-?-transformed cells. Our studies established a distinctive involvement of PKC? in epithelial and mesenchymal NSCLC cells, and identified a complex interplay between PKC? and small GTPases that contributes to regulation of NSCLC cell morphology and motile activity.

SUBMITTER: Casado-Medrano V 

PROVIDER: S-EPMC6609469 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature