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

• Main Authors: Miaki Uzu, Hiromi Sato, Ayaka Shimizu, Yukihiro Shibata, Koichi Ueno, Akihiro Hisaka
• Format: Article
• Language: English
• Published: Elsevier 2017-06-01
• Series: Journal of Pharmacological Sciences
• Subjects: Connexin; Bax; Mitochondria; Apoptosis; JNK
• Online Access: http://www.sciencedirect.com/science/article/pii/S1347861317300798

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.