Connexin 43 enhances Bax activation via JNK activation in sunitinib-induced apoptosis in mesothelioma cells

Abstract

The constituent protein of gap junctions, connexin (Cx), interacts with various proteins via its C-terminus region, including kinases, cell-adhesion proteins, and a pro-apoptotic protein, Bax. This molecular interaction may affect expression and functioning of the interacting proteins and modulate the cellular physiology. In our previous work, Cx43 was found to interact directly with Bax and in the presence of sunitinib, lead to the Bax-mediated apoptosis in mesothelioma cells. In this study, we investigated the mechanism of how Cx43 promotes Bax-mediated apoptosis using the same cell line. Treatment with sunitinib increased the expression of the active conformation of the Bax protein, which was predominantly localized at the mitochondria, only in Cx43-transfected cells. Bax oligomerization and decrease in the mitochondrial membrane potential were also observed. The involvement of c-Jun N-terminal kinase (JNK) in the interaction of Cx43 and Bax was further examined. Treatment with sunitinib increased the expression of phosphorylated (active) form of JNK only in the Cx43-transfected cells. Phosphorylated JNK and active Bax were co-localized, and the co-localization was suppressed by the knockdown of Cx43. Moreover, JNK inhibition clearly suppressed Bax activation. In conclusion, we identified a novel Cx43-JNK-Bax axis regulating the process of apoptosis for the first time.

Changes in the expression of interleukin-10 in myocardial infarction and its relationship with macrophage activation and cell apoptosis

“…On day 7 of myocardial infarction, inflammatory cell infiltration in the infarcted areas was more significant. Among them, the expression of MCP-1 protein showed a peak, blocking the apoptotic pathway and inhibiting the occurrence of apoptosis [5,21]. However, the ratio of Bcl-2/Bax is closely related to cell apoptosis and survival [6,22].…”

Conflicting Roles of Connexin43 in Tumor-Induced Inflammation and Cancer Pathology

“…Increasing level of Cx43 in malignant mesothelioma cell enhances sensitivity against cisplatin and sunitinib treatment [11], [12], [13],…”

“…Cx43 is also known to promote migration through channel-independent mechanisms; it strengthens adhesive connections between glioma cells and astrocytes via its extracellular loops (67,68,73,74), and also regulates cytoskeletal dynamics via its carboxy (C)-terminal tail (75)(76)(77). The C-tail of Cx43 interacts with various intracellular signaling molecules (12,76,78,79) and serves a role in channel gating (60,80,81).…”

“…The pivotal role of Cx43 in promoting tumor progression has been previously overlooked because downregulation of Cx43-mediated intercellular communication is normally associated with increased malignancy in tumor cells (5,6). Indeed, for a long period, it was believed that the GJ formed by Cx43 has mostly tumor suppressive effects (5)(6)(7), such as its role in anti-proliferation (8,9), anti-metastasis (10), and pro-apoptosis (11)(12)(13)(14)(15). In contrast, emerging evidence indicates that Cx43 serves a facilitative role in tumorigenesis (5,16), especially in advanced stages (7).…”

“…cells to temozolomide treatment by modulating the mitochondrial apoptosis pathway(86). In addition, Cx43 interacts with Bax in the vicinity of the cell membrane, and by promoting its mitochondrial transition, it regulates the apoptotic signal of the cell and enhances sunitinib susceptibility(12). We will next review examples distinguishing whether the GJs mediate effects via homocellular-type or heterocellular-type of interactions in the multiple steps of cancer invasion.…”