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Protein Kinase C Is Required for Epidermal Growth Factor–Induced Chemotaxis of Human Breast Cancer Cells

¹ Department of Chemical Biology and State Key Laboratory of Molecular Dynamic and Stable Structures, College of Chemistry and ² Laboratory of Medical Immunology, School of Basic Medical Science, Peking University, Beijing, China; and ³ Laboratory of Molecular Immunoregulation, Center for Cancer Research, Intramural Research Support Program, National Cancer Institute, Frederick, Maryland

Requests for reprints: Ning Zhang, Department of Chemical Biology and State Key Laboratory of Molecular Dynamic and Stable Structures, College of Chemistry, Peking University, Beijing 100871, P.R. China. Phone: 86-10-62755154; Fax: 86-10-62751708; E-mail: zhangnz{at}pku.edu.cn.

Chemotaxis plays an important role in cancer cell metastasis. In this study, we showed that epidermal growth factor (EGF) was a more potent chemoattractant than chemokine SDF-1/CXCL12 for human breast cancer cell MDA-MB-231. Different inhibitors were used to evaluate the involvement of 12 protein kinase C (PKC) isotypes in the chemotactic signaling pathway. Chelerythrine chloride, an inhibitor of all PKC isotypes, blocked chemotaxis, whereas inhibitors of classic and novel PKC, such as Gö6976, Gö6850, or calphostin C, only impaired EGF-induced chemotaxis to a minor extent by 32% inhibition. These data suggested that atypical PKC were involved. The ligand-induced actin polymerization and cell adhesion were also similarly dependent on atypical PKC. Immunofluorescent staining showed an EGF-induced, LY294002-sensitive translocation of PKC from the cytosol to the plasma membrane, indicating that EGF was capable of activating PKC, probably via phosphoinositide 3 kinases. A myristoylated PKC pseudosubstrate blocked the chemotaxis with an IC₅₀ of 20 µmol/L. To expand our investigation, we further showed that in MCF-7 and T47D, two additional human breast cancer cell lines, EGF-activated PKC and the PKC pseudosubstrate, inhibited chemotaxis. Taken together, our data suggest that PKC is an essential component of the EGF-stimulated chemotactic signaling pathway in human breast cancer cells.

Key Words: chemotaxis • EGF • PKC • metastasis

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