Ouabain Promotes Gap Junctional Intercellular Communication in Cancer Cells.

Mauricio Serrano-Rubi,Lidia Jimenez,Marcelino Cereijido,Jacqueline Martinez-Rendon,Arturo Ponce

doi:10.3390/ijms22010358

Abstract

Gap junctions are molecular structures that allow communication between neighboring cells. It has been shown that gap junctional intercellular communication (GJIC) is notoriously reduced in cancer cells compared to their normal counterparts. Ouabain, a plant derived substance, widely known for its therapeutic properties on the heart, has been shown to play a role in several types of cancer, although its mechanism of action is not yet fully understood. Since we have previously shown that ouabain enhances GJIC in epithelial cells (MDCK), here we probed whether ouabain affects GJIC in a variety of cancer cell lines, including cervico-uterine (CasKi, SiHa and Hela), breast (MDA-MB-321 and MCF7), lung (A549), colon (SW480) and pancreas (HPAF-II). For this purpose, we conducted dye transfer assays to measure and compare GJIC in monolayers of cells with and without treatment with ouabain (0.1, 1, 10, 50 and 500 nM). We found that ouabain induces a statistically significant enhancement of GJIC in all of these cancer cell lines, albeit with distinct sensitivity. Additionally, we show that synthesis of new nucleotides or protein subunits is not required, and that Csrc, ErK1/2 and ROCK-Rho mediate the signaling mechanisms. These results may contribute to explaining how ouabain influences cancer.

Highlights

Ouabain is a compound of remarkable interest that—because of its chemical properties—has been useful to humans for a long time, formerly for hunting and war purposes and later as a medicine to treat hypotension and cardiac arrhythmias
It is known that there is a relationship between gap junctional intercellular communication (GJIC) and cancer, until now, whether cardiac glycosides influence GJIC in cancer cells has not been explored
In this work we tested whether ouabain influences GJIC in a variety of cell lines derived from cancer of cervical origin, breast, lung, colon and pancreas

Summary

Introduction

Ouabain is a compound of remarkable interest that—because of its chemical properties—has been useful to humans for a long time, formerly for hunting and war purposes and later as a medicine to treat hypotension and cardiac arrhythmias. In addition to the well-known effects of ouabain on the cardiovascular system and blood pressure control, compelling findings have revealed new roles in fundamental cellular aspects, such as proliferation, apoptosis, cell adhesion, differentiation and migration [9,10]. These findings have led to ouabain being considered as a promising novel therapeutic agent to fight cancer [11,12]

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Conclusion