Down-regulation of PKCzeta 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 Gö6976, calphostin C, or Gö6850, 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 PKCzeta, indicating that EGF could activate PKCzeta. Treatment with a PKCzeta specific inhibitor, a myristoylated pseudosubstrate, blocked the chemotaxis in a dose-dependent manner, further confirming that atypical PKCzeta was required for NSCLC chemotaxis. Mechanistic studies suggested that PKCzeta was regulated by phosphatidylinositol 3 kinase (PI3K)/Akt. Furthermore, PKCzeta-mediated chemotaxis by regulating actin polymerization and cell adhesion. Taken together, our study suggested that PKCzeta was required in NSCLC cell chemotaxis, thus could be used as a target to develop anti-lung cancer metastasis therapies.
Liu
Ying
Y
Beijing National Laboratory for Molecular Sciences (BNLMS), Department of Chemical Biology, Peking University, Beijing 100871, China.
Wang
Bing
B
Wang
Jingna
J
Wan
Wuzhou
W
Sun
Ronghua
R
Zhao
Yuliang
Y
Zhang
Ning
N
D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects*; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000099221:Protein Kinase C zeta
D054377:Chemokine CXCL12; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; D000099221:Protein Kinase C zeta; C527276:CXCR4 protein, human