Non-small cell lung carcinoma cell motility, rac activation and metastatic dissemination are mediated by protein kinase C epsilon

• Published in: PloS one 2012-02, Vol.7 (2), p.e31714-e31714
• Main Authors: Caino, M Cecilia, Lopez-Haber, Cynthia, Kissil, Joseph L, Kazanietz, Marcelo G
• Format: Article
• Language: English
• Subjects: Acetic acid; Activation; Analysis; Animals; Apoptosis; B cells; Biology; Cancer; Cancer metastasis; Carcinoma - metabolism; Carcinoma - pathology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell activation; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell migration; Cell Movement; Cell survival; Development and progression; Disease Progression; Enzyme Activation; Epidermal growth factor; Epidermal growth factors; Extracellular matrix; Extracellular Matrix - metabolism; Gene Expression Regulation, Neoplastic; Growth factors; Guanosine triphosphatases; Guanosine Triphosphate - metabolism; Guanosinetriphosphatase; Humans; Invasiveness; Kinases; Lopez, Cynthia; Lung cancer; Lung carcinoma; Lung diseases; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Male; Medicine; Metastases; Metastasis; Mice; Mice, Nude; Motility; Neoplasm Metastasis; Non-small cell lung cancer; Non-small cell lung carcinoma; Pharmacology; Phorbol 12-myristate 13-acetate; Phosphorylation; Physics; Protease inhibitors; Proteases; Protein kinase C; Protein Kinase C-epsilon - metabolism; Protein kinases; Proteinase inhibitors; Proteins; rac GTP-Binding Proteins - metabolism; Rac1 protein; RNA Interference; RNA-mediated interference; Secretion; Signal Transduction; Signaling; Small cell lung carcinoma; Therapeutic applications
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031714

Protein kinase C (PKC) ε, 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 PKCε in lung cancer metastasis has not yet been established. Here we show that RNAi-mediated knockdown of PKCε 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). PKCε depletion markedly impaired the ability of NSCLC cells to form membrane ruffles and migrate. Similar results were observed by pharmacological inhibition of PKCε with εV1-2, a specific PKCε inhibitor. PKCε was also required for invasiveness of NSCLC cells and modulated the secretion of extracellular matrix proteases and protease inhibitors. Finally, we found that PKCε-depleted NSCLC cells fail to disseminate to lungs in a mouse model of metastasis. Our results implicate PKCε as a key mediator of Rac signaling and motility of lung cancer cells, highlighting its potential as a therapeutic target.