Connexins and cAMP Cross-Talk in Cancer Progression and Metastasis

Abstract

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.

Keywords: cAMP; cancer; connexin; metastasis.

Figure 1

Regulation of connexin (Cx) expression by cAMP/PKA signaling in modulating cancer cell growth and primary cancer progression. The schematic illustrates the mechanism involved in the cAMP signaling-mediated regulation of Cx levels. Activation of the G-protein-coupled receptor on the cell membrane by ligands leads to cAMP synthesis by AC. cAMP diffuses into the cell and activates its effector protein PKA, which phosphorylates NF-κB. Subsequently, NF-κB, CBP, and CREB form a complex to regulate the transcription of Cxs [25,42,43,44]. Abbreviations: AC, adenylyl cyclase; PKA, protein kinase A; NF-κB, nuclear factor kappa-B; CBP, CREB-binding protein; CREB, cAMP response element-binding protein; PKI, PKA inhibitor; and ICER, inducible cAMP early repressor I.

Figure 2

cAMP/PKA signaling mediates the phosphorylation of connexins (Cxs) to promote cancer cell migration and malignant transformation. In the resting state (left panel), the whole complex consists of Cx, ZO-1, Ezrin, and a PKA pool anchored by Cx-bound ezrin. When cAMP levels increase (right panel), PKA regulatory subunits bind to four cAMP molecules, resulting in activated PKA catalytic subunits, increased Cx phosphorylation, and gap junction-mediated intercellular coupling [26,53,54,55]. Abbreviations: RIIα, PKA regulatory subunits and PKA C, PKA catalytic subunits.

Figure 3

Gap junction-mediated transfer of cAMP limits the rate of mitosis of the whole tumor cell population. Changes in cAMP levels alter PKA activity to regulate cell cycle progression. Low levels of PKA activity help cells progress through the G1 and S phases to interphase. However, high levels of PKA activity are needed for cells to enter and exit the mitotic cycle. In the absence of gap junction-mediated communication, different cAMP levels in each cell result in different cell cycle stages in the population. However, the cell groups that maintain communication throughout the cell cycle exhibit a uniform distribution of cAMP, thereby, resulting in the dilution of cAMP (and decrease in P-PKA) in M-phase cells (leading to the inhibition of mitotic processes) and an increase in cAMP and PKA activity in G1/S-phase cells (leading to partial G1 phase arrest). Thus, cAMP redistribution delays the M phase and cell cycle progression through the interphase [21,63].