Down-regulation of PKCζ expression inhibits chemotaxis signal transduction in human lung cancer cells

Metastasis is the major cause of mortality in lung cancer. Chemotaxis plays a vital role in cancer cell metastasis. In the current study, we reported that epidermal growth factor (EGF) induced a robust chemotaxis of A549 and H1299 cells, two representative human non-small cell lung cancer (NSCLC) cells. Chelerythrine chloride, an inhibitor of all protein kinase C (PKC) isozymes, significantly reduced the chemotactic capacity of NSCLC cells while inhibitors of classical or novel PKC isozymes, such as 666976, calphostin C, or Go6850, showed no effect, which suggested that atypical PKC might be involved in the chemotactic process of NSCLC cells. EGF-elicited translocation and phosphorylation of atypical PKC, indicating that EGF could activate PKC zeta. Treatment with a PKC zeta specific inhibitor, a myristoylated pseudosubstrate, blocked the chemotaxis in a dose-dependent manner, further confirming that atypical PKCI; was required for NSCLC chemotaxis. Mechanistic studies suggested that PKC zeta; was regulated by phosphatidylinositol 3 kinase (PI3K)/Akt. Furthermore, PKC zeta-mediated chemotaxis by regulating actin polymerization and cell adhesion. Taken together, our study suggested that PKC zeta was required in NSCLC cell chemotaxis, thus could be used as a target to develop anti-lung cancer metastasis therapies. (C) 2008 Published by Elsevier Ireland Ltd.