Connexins and cAMP Cross-Talk in Cancer Progression and Metastasis

Simple Summary: Different connexins play diverse roles in cancers, either tumor-suppressing or tumor-promoting. In lung cancer, Cx43 serves as a tumor suppressor at the early stage, but it can also be a tumor-promotor at an advanced stage and during metastasis. Moreover, other connexins, including Cx26, Cx31.1, and Cx32, can be tumor suppressors. In contrast, Cx30.3 can be a tumor-promotor. The roles of different connexins in different cancers have also been established. Cx43 acts as a tumor suppressor in colorectal cancer, breast cancer, and glioma, whereas Cx32 can be a suppressor in liver tumors and hepatocarcinogenesis. Cx26 can be a tumor suppressor in mammary tumors; in contrast, it can be a tumor-promotor in melanoma. Existing drugs/molecules targeting the cAMP/PKA/connexin axis act to regulate channel opening/closing. Mimic peptides, such as Gap19, Gap26, and Gap 27 block hemichannels, mimetic peptides, and CT9/CT10 and promote hemichannel opening and also hemichannel closing. Connexin-containing gap junctions mediate the direct exchange of small molecules between cells, thus promoting cell-cell communication. Connexins (Cxs) have been widely studied as key tumor-suppressors. However, certain Cx subtypes, such as Cx43 and Cx26, are overexpressed in metastatic tumor lesions. Cyclic adenosine monophosphate (cAMP) signaling regulates Cx expression and function via transcriptional control and phosphorylation. cAMP also passes through gap junction channels between adjacent cells, regulating cell cycle progression, particularly in cancer cell populations. Low levels of cAMP are sufficient to activate key effectors. The present review evaluates the mechanisms underlying Cx regulation by cAMP signaling and the role of gap junctions in cancer progression and metastasis. A deeper understanding of these processes might facilitate the development of novel anticancer drugs.