Title:A Cell-Cell Communication Marker for Identifying Targeted Tumor Therapies
VOLUME: 9 ISSUE: 3
Author(s):Diane F. Matesic, Amna Ali, Tatyana S. Sidorova and Timothy J. Burns
Affiliation:Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341.
Keywords:Gap junction, p38 MAPK, JNK, Akt kinase.
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 or ras-transformed epithelial cells. Western blotting using connexinspecific
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 kinase in vitro as 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.
