title: Effect of enhanced expression of connexin 43 on sunitinib-induced cytotoxicity in mesothelioma cells.
abstract: Connexin (Cx) makes up a type of intercellular channel called gap junction (GJ). GJ plays a regulatory role in cellular physiology. The Cx expression level is often decreased in cancer cells compared to that in healthy ones, and the restoration of its expression has been shown to exert antiproliferative effects. This work aims to evaluate the effect of the restoration of connexin 43 (Cx43) (the most ubiquitous Cx subtype) expression on sunitinib (SU)-induced cytotoxicity in malignant mesothelioma (MM) cells. Increased Cx43 expression in an MM cell line (H28) improved the ability of SU to inhibit receptor tyrosine kinase (RTK) signaling. Moreover, higher Cx43 expression promoted SU-induced apoptosis. The cell viability test revealed that Cx43 enhanced the cytotoxic effect of SU in a GJ-independent manner. The effect of Cx43 on a proapoptotic factor, Bax, was then investigated. The interaction between Cx43 and Bax was confirmed by immunoprecipitation. Furthermore, higher Cx43 expression increased the production of a cleaved (active) form of Bax during SU-induced apoptosis with no alteration in total Bax expression. These findings indicate that Cx43 most likely increases sensitivity to SU in H28 through direct interaction with Bax. In conclusion, we found that Cx43 overcame the chemoresistance of MM cells.
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba 260-8675, Japan.
authors.forename: Miaki
authors.initials: M
authors.lastname: Uzu
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba 260-8675, Japan. Electronic address: hiromi-s@chiba-u.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba 260-8675, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba 260-8675, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kashiba
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba 260-8675, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba 260-8675, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yamaura
authors.affiliation: Center for Preventive Medical Science, Chiba University, 1-8-1 Inohana, Chuo-ward, Chiba-city, Chiba 260-8675, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D018031:Connexin 43 / Q000235:genetics* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D017629:Gap Junctions / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D018031:Connexin 43; D007211:Indoles; D011758:Pyrroles; D051028:bcl-2-Associated X Protein; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib
keywords: Chemotherapy; Connexin; Drug resistance; Mesothelioma; Sunitinib