Connexin43 Suppresses Lung Cancer Stem Cells.

Randall Ruch

doi:10.3390/cancers11020175

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.

Highlights

Cancer stem cells (CSCs) are a population of cells that have high tumorigenic potential, self-renewal capacity, and resistance to therapy [1,2]
We previously reported that H125 express negligible for functional junctions, thejunctions
Since tumorspheres may originate from CSCs [30], these results suggest Cx43

Summary

Introduction

Cancer stem cells (CSCs) are a population of cells that have high tumorigenic potential, self-renewal capacity, and resistance to therapy [1,2]. The intense study of CSCs over the past two decades has led to a much greater understanding of their biology. Whether gap junctions and their protein components (connexins) are expressed in CSCs and how this impacts the CSC phenotype, including resistance to treatment, has not been widely investigated. Gap junctions are intercellular junctions present in all human tissues and consist of plasma membrane-localized clusters of aqueous channels that connect the interiors of adjacent cells. The channels are comprised of proteins known as connexins of which there are 20 human forms. The channels are approximately 1.5 nm in diameter and allow molecules less than approximately

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