Inhibition of NHE-1 Increases Smoke-Induced Proliferative Activity of Barrett’s Esophageal Cell Line

Abstract

Several clinical studies indicate that smoking predisposes its consumers to esophageal inflammatory and malignant diseases, but the cellular mechanism is not clear. Ion transporters protect esophageal epithelial cells by maintaining intracellular pH at normal levels. In this study, we hypothesized that smoking affects the function of ion transporters, thus playing a role in the development of smoking-induced esophageal diseases. Esophageal cell lines were treated with cigarettesmoke extract (CSE), and the viability and proliferation of the cells, as well as the activity, mRNA and protein expression of the Na+/H+ exchanger-1 (NHE-1), were studied. NHE-1 expression was also investigated in human samples. For chronic treatment, guinea pigs were exposed to tobacco smoke, and NHE-1 activity was measured. Silencing of NHE-1 was performed by using specific siRNA. CSE treatment increased the activity and protein expression of NHE-1 in the metaplastic cells and decreased the rate of proliferation in a NHE-1-dependent manner. In contrast, CSE increased the proliferation of dysplastic cells independently of NHE-1. In the normal cells, the expression and activity of NHE-1 decreased due to in vitro and in vivo smoke exposure. Smoking enhances the function of NHE-1 in Barrett’s esophagus, and this is presumably a compensatory mechanism against this toxic agent.

The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity

“…It is feasible that the observed morphological alterations in the nhe1 −/− mucosa are early signs of chronic acid damage, and that the short lifespan of the mice prevented the development of more obvious changes, as observed in the gastric mucosa of carbonic anhydrase IX-deficient mice ( Gut et al, 2002 ; Li et al, 2018 ). Indeed, a recent publication emphasizes the protective role of NHE1 in the esophagus during environmental stress and suggests an anti-proliferative function in pre-malignancy ( Becskeházi et al, 2021 ).…”

30-Min Exposure to Tobacco Smoke Influences Airway Ion Transport—An In Vitro Study

“…Tumor transformation is associated with the changes in sodium and potassium transport from blood and through intracellular membranes [9,20]. These changes are crucial to the cancer reprogramming of cells that contribute to cancer initiation, progression, tumor proliferation, metastasis, and resistance to anticancer therapy [20,21]. Changing the activity of selected channels and the transport of those ions to and from respiratory epithelial cells can be used to develop new therapeutic strategies, for example by re-targeting already existing drugs that are known to target potassium channels [21,22].…”