Human
lung neoplasms frequently express mutations that down-regulate expression of various
tumor suppressor molecules, including
mitogen-activated protein kinases such as
p38 MAPK. Conversely, activation of
p38 MAPK in
tumor cells results in
cancer cell cycle inhibition or apoptosis initiated by chemotherapeutic agents such as
retinoids or
cisplatin, and is therefore an attractive approach for experimental anti-
tumor therapies. We now report that
4-phenyl-3-butenoic acid (PBA), an experimental compound that reverses the transformed phenotype at non-cytotoxic concentrations, activates
p38 MAPK in tumorigenic cells at concentrations and treatment times that correlate with decreased cell growth and increased cell-cell communication. H2009 human lung
carcinoma cells and ras-transformed rat liver epithelial cells treated with PBA showed increased activation of
p38 MAPK and its downstream effectors which occurred after 4 h and lasted beyond 48 h. Untransformed plasmid control cells showed low activation of
p38 MAPK compared to ras-transformed and H2009
carcinoma cells, which correlates with the reduced effect of PBA on untransformed cell growth. The
p38 MAPK inhibitor,
SB203580, negated PBA's activation of
p38 MAPK downstream effectors. PBA also increased cell-cell communication and
connexin 43 phosphorylation in ras-transformed cells, which were prevented by
SB203580. In addition, PBA decreased activation of JNK, which is upregulated in many
cancers. Taken together, these results suggest that PBA exerts its growth regulatory effect in tumorigenic cells by concomitant up-regulation of
p38 MAPK activity, altered
connexin 43 expression, and down-regulation of JNK activity. PBA may therefore be an effective therapeutic agent in human
cancers that exhibit down-regulated
p38 MAPK activity and/or activated JNK and altered cell-cell communication.