Non-Small Cell Lung Carcinoma Cell Motility, Rac Activation and Metastatic Dissemination Are Mediated by Protein Kinase C Epsilon

Background: Protein kinase C (PKC) epsilon, a key signaling transducer implicated in mitogenesis, survival, and cancer progression, is overexpressed in human primary non-small cell lung cancer (NSCLC). The role of PKC epsilon in lung cancer metastasis has not yet been established. Principal Findings: Here we show that RNAi-mediated knockdown of PKC epsilon in H358, H1299, H322, and A549 NSCLC impairs activation of the small GTPase Rac1 in response to phorbol 12-myristate 13-acetate (PMA), serum, or epidermal growth factor (EGF). PKC epsilon depletion markedly impaired the ability of NSCLC cells to form membrane ruffles and migrate. Similar results were observed by pharmacological inhibition of PKC epsilon with epsilon V1-2, a specific PKC epsilon inhibitor. PKC epsilon was also required for invasiveness of NSCLC cells and modulated the secretion of extracellular matrix proteases and protease inhibitors. Finally, we found that PKC epsilon-depleted NSCLC cells fail to disseminate to lungs in a mouse model of metastasis. Conclusions: Our results implicate PKC epsilon as a key mediator of Rac signaling and motility of lung cancer cells, highlighting its potential as a therapeutic target.