Effect of enhanced expression of connexin 43 on sunitinib-induced cytotoxicity in mesothelioma cells

Miaki Uzu, Hiromi Sato, Ryota Yamada, Tatsuro Kashiba, Yukihiro Shibata, Katsunori Yamaura, Koichi Ueno

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)17-26
Number of pages10
JournalJournal of Pharmacological Sciences
Volume128
Issue number1
DOIs
Publication statusPublished - 2015 May 1
Externally publishedYes

Keywords

  • Chemotherapy
  • Connexin
  • Drug resistance
  • Mesothelioma
  • Sunitinib

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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