Connexin43 Suppresses Lung Cancer Stem Cells

Abstract

Alterations in gap junctions and their protein components, connexins, have been associated with neoplastic transformation and drug resistance, and more recently have been shown to play important roles in cancer stem cells (CSCs). However, there is less knowledge of connexins and gap junctions in lung CSCs. To address this, Connexin43 (Cx43), the major human lung epithelial gap junction protein, was expressed ectopically in poorly expressing National Cancer Institute-125 (NCI-H125) metastatic human lung adenocarcinoma cells, and phenotypic characteristics of malignant cells and abundance of CSCs were evaluated. The ectopic expression of Cx43 resulted in the formation of functional gap junctions; a more epithelial morphology; reduced proliferation, invasion, colony formation, tumorsphere formation, pluripotency marker expression, and percentage of aldehyde dehydrogenase (ALDH)-positive cells; and increased cisplatin sensitivity. Similarly, in NCI-H522 (human lung adenocarcinoma) and NCI-H661 (human lung large cell carcinoma) cell lines, which express Cx43 and functional gap junctions endogenously, the Cx43 content was lower in tumorspheres and ALDH-positive cells than in bulk cells. These results demonstrate that Cx43 can reverse several neoplastic characteristics and reduce the abundance of human lung CSCs.