Search

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.

Chemotaxis plays an important role in metastasis of cancer cells. In the current study, we investigated the role of PTEN, a tumor suppressor, in chemotaxis of human breast cancer cells. Over-expression of PTEN inhibited EGF-induced chemotaxis, probably due to an overall reduction of PIP3 levels. Disruption of PTEN by siRNA caused a marked decrease in chemokinesis, cell adhesion, and membrane spreading, resulting in a severe defect in chemotaxis. In PTEN disrupted cells, PDK1, AKT, and PKCζ exhibited elevated basal activities, which prevented EGF-induced further activation of these molecules. In the absence of EGF, active PDK1 was detected on multiple directions of the plasma membranes of PTEN disrupted cells, which competed against EGF-induced gradient sensing. To confirm the biological relevance of in vitro studies, both PTEN disrupted cells and its parental human breast cancer cells were injected into tail veins of SCID mice. Mice injected with PTEN disrupted cancer cells showed a marked decrease in lung metastasis. Taken together, our data show that PTEN plays a non-redundant role in EGF-induced chemotaxis of human breast cancer cells, and an optimal level of PTEN is required in these responses.