Screening of a PKC zeta-specific kinase inhibitor PKCzI257.3 which inhibits EGF-induced breast cancer cell chemotaxis.

Chemotaxis has recently been implicated in tumor metastasis. Protein Kinase C(PKC)zeta is often over-activated and is a key signal transducer shared by both EGFR- and CXCR4-mediated chemotactic signaling in human breast and lung cancers, as well as CSF-1-induced macrophage migration. In order to develop potential inhibitors targeting PKCzeta for effective blockage of cancer cell chemotaxis and tumor metastasis, the Z'-lyte kinase assay -SER/THR 7 peptide kit was used and a compound called PKCzI257.3 was identified with IC50 of 28 microM. As a result of treatment, chemotactic migration potency of the human breast cancer cell MDA-MB-231 were impaired, while no significant effect was observed on cell proliferation. Furthermore, EGF-induced cofilin phosphorylation, a critical step of cofilin recycle and actin polymerization, was also dampened, which was relevant to the decreased cell migration. Our results suggest that PKCzI257.3 is a PKCzeta-specific compound inhibitor which blocked cancer cell migration and may serve as a potential therapeutic drug for cancer treatment.