Abstract
Melanoma cells preserve intracellular pH (pHi) within a viable range despite an acidic ambient pH that typically falls below pH 7.0. The molecular mechanisms underlying this form of acidic preservation in melanoma remain poorly understood. Previous studies had demonstrated that proton transporters including the monocarboxylate transporter (MCT), the sodium hydrogen exchanger (NHE), and V-Type ATPase mediate acid extrusion to counter intracellular acidification in melanoma cells. In this report, the expression and function of the Sodium-Coupled Bicarbonate Transporter (NCBT) family of base loaders were further characterized in melanoma cell lines. NCBT family members were found to be expressed in three different melanoma cell lines – A375, MeWo, and HS695T – and included the electrogenic sodium-bicarbonate cotransporter isoforms 1 and 2 (NBCe1 and NBCe2), the electroneutral sodium-bicarbonate cotransporter (NBCn1), and the sodium-dependent chloride-bicarbonate exchanger (NDCBE). These transporters facilitated 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS)-dependent pHi recovery in melanoma cells, in response to intracellular acidification induced by ammonium chloride prepulse. Furthermore, the expression of NCBTs were upregulated via chronic exposure to extracellular acidification. Given the current research interest in the NCBTs as a molecular driver of tumourigenesis, characterising NCBT in melanoma provides impetus for developing novel therapeutic targets for melanoma treatment.
Highlights
This study further showed that the expression of NCBTs in A375 melanoma cells could be upregulated by the exposure to chronic acidity, a relevant pathophysiological feature of NCBT’s regulation in melanoma cells
This study demonstrated that A375 human melanoma cells exposed to acidic stress relied on functional NCBTs, as well as different modalities of proton transporters to maintain their pHi balance
This study showed that under acidic stress, the sustenance of pHi within the viable range contributed to cellular proliferation and viability in A375 melanoma cells
Summary
One major acid extruder protein family that has remained poorly characterised to date in melanoma cells is the sodium-coupled bicarbonate transporter (NCBT) family of pHi regulators[4]. Electrogenic NCBTs (NBCe1 and NBCe2) cotransport Na+ and HCO−3 in a 1:2 or 1:3 stoichiometric ratio[18] Such transport activity results in the net movement of 1–2 negative charges across the cell membrane per transport cycle[23]. A375 cells kept pHi within the viable range via an endergonic reaction that was significantly curtailed upon serum deprivation This observation prompted a further search for active acid extrusion mechanisms that were responsible for preserving pHi in melanoma cells, and yielded definitive evidence of NCBT’s expression and function in melanoma cells. This study further showed that the expression of NCBTs in A375 melanoma cells could be upregulated by the exposure to chronic acidity, a relevant pathophysiological feature of NCBT’s regulation in melanoma cells
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