title: A Cell-Cell Communication Marker for Identifying Targeted Tumor Therapies.
abstract: Cell-cell communication through gap junctions is aberrant or absent in a majority of human cancer cells, compared to cells in corresponding normal tissues. This and other evidence has led to the hypothesis that gap junction channels, comprised of connexin proteins, are important in growth control and cancer progression. The major goal of this ongoing study was to identify bioactive compounds that specifically upregulate gap junction channel-mediated cell-cell communication as potential anti-tumor therapies. Control of cell-cell communication is linked to growth regulatory intracellular signaling pathways; we therefore further aimed to identify signaling pathways modulated by these compounds in order to assess their potential as targeted anti-tumor therapies. Compounds were screened for their ability to upregulate gap junction-mediated cell-cell communication by using a fluorescent dye transfer assay to measure cell-cell communication between tumor promoter-treated astroglial cells orras-transformed epithelial cells. Western blotting using connexin-specific and phosphorylation site-specific antibodies was used to monitor phosphorylation changes in signaling pathway proteins. Our results identified three compounds that upregulate gap junction-mediated cell-cell communication in our screening assays, chaetoglobosin K(ChK), 4-phenyl-3-butenoic acid (PBA) and the methyl ester of PBA (PBA-Me). Further analyses demonstrated that in tumorigenic cells, ChK downregulates phosphorylation of Akt kinase, an enzyme in the PI3-kinase signaling pathway that is found to be upregulated in a number of human cancers, on a key activation site. However, ChK did not inhibit PI-3 kinasein vitroas did the classic PI-3 kinase inhibitor, Wortmannin. PBA and PBA-Me were found to upregulate phosphorylation of p38 MAPK on a key activation site in tumorigenic cells, which is downregulated in several human cancer cell types. ChK and PBA also decreased activation of SAPK/JNK, another kinase found to be upregulated in a number of human cancers. These studies highlight the potential of monitoring gap junction intercellular communication for identifying experimental anti-tumor compounds.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University Atlanta, Georgia 30341.
authors.forename: Diane F
authors.initials: DF
authors.lastname: Matesic
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University Atlanta, Georgia 30341.
authors.forename: Amna
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University Atlanta, Georgia 30341.
authors.forename: Tatyana S
authors.initials: TS
authors.lastname: Sidorova
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University Atlanta, Georgia 30341.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Burns
keywords: Akt kinase; Gap junction; JNK; p38 MAPK