Loss of gap junctional intercellular communication (GJIC) between
cancer cells is a common characteristic of malignant transformation. This communication is mediated by
connexin proteins that make up the functional units of gap junctions.
Connexins are highly regulated at the
protein level and phosphorylation events play a key role in their trafficking and degradation. The
metastasis suppressor
breast cancer metastasis suppressor 1 (BRMS1) upregulates GJIC and decreases phosphoinositide-3-kinase (PI3K) signaling. On the basis of these observations, we set out to determine whether there was a link between PI3K and GJIC in tumorigenic and metastatic cell lines. Treatment of cells with the well-known PI3K inhibitor
LY294002, and its structural analogue
LY303511, which does not inhibit PI3K, increased homotypic GJIC; however, we found the effect to be independent of PI3K/AKT inhibition. We show in multiple
cancer cell lines of varying metastatic capability that GJIC can be restored without enforced expression of a
connexin gene. In addition, while levels of
connexin 43 remained unchanged, its relocalization from the cytosol to the plasma membrane was observed. Both
LY294002 and
LY303511 increased the activity of
protein kinase A (PKA). Moreover, PKA blockade by the small molecule inhibitor
H89 decreased the
LY294002/
LY303511-mediated increase in GJIC. Collectively, our findings show a connection between PKA activity and GJIC mediated by PI3K-independent mechanisms of
LY294002 and
LY303511. Manipulation of these signaling pathways could prove useful for antimetastatic
therapy.