title: J-4:  a novel and typical preclinical anticancer drug targeting protein kinase C ζ.
abstract: Metastasis is the major cause of morbidity and mortality from breast cancer. Cell motility and chemotaxis play important roles in the metastatic cascade of cancer cells. Protein kinase C ζ (PKCζ) mediates cancer cell chemotaxis by regulating cytoskeleton rearrangement and cell adhesion. In the current study, we investigated the inhibitory effect of a compound called J-4 targeting PKCζ. J-4 was tested with inhibitory concentration (IC(50)) of 10 µmol/l using a Z'-LYTE™ Kinase Assay-Ser/Thr 7 Peptide Kit. Our results show that J-4 inhibited spontaneous migration and epidermal growth factor (EGF)-induced chemotaxis of human breast cancer cell MDA-MB-231. Through an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the drug designated as J-4 had no obvious cytotoxicity in vitro. Meanwhile, in the presence of J-4, the cells showed defects in EGF-induced actin polymerization and adhesion. Furthermore, J-4 dampened EGF-induced phosphorylation and recycling of cofilin. Taken together, our data demonstrate that J-4 is a new and typical inhibitor that blocks the PKCζ pathway. Moreover, a better understanding of the mechanism of action of J-4 may provide a novel medical therapeutic strategy for cancer treatment that would block metastasis, thereby reducing the proliferation and dissemination of cancer cells and increasing patient survival.
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Guoguang
authors.initials: G
authors.lastname: Ying
authors.forename: Liwei
authors.initials: L
authors.lastname: Chen
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
mesh_terms: D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000578:Amidines / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001555:Benzene Derivatives / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D009362:Neoplasm Metastasis / Q000517:prevention & control; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000099221:Protein Kinase C zeta
chemical_list: D000199:Actins; D000578:Amidines; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C576533:J-4 compound