NHE1, NHE2, and NHE4 contribute to regulation of cell pH in T84 colon cancer cells

Beltrán, Ana Rosa; Ramírez, M. A.; Carraro‐Lacroix, Luciene Regina; Hiraki, Yumi; Rebouças, Nancy Amaral; Malnic, Gerhard

doi:10.1007/s00424-007-0333-0

Cited by 41 publications

(59 citation statements)

References 41 publications

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“…This phenomenon depends on the expression of membrane transport systems for H + removal [8,33]. haOC cells show pHi cells (~31 (mmol/L)/pHi units) [22,35], and lower than in non-tumour MDCK cells (~110 (mmol/L)/pHi units) [21]. The differences in the βi values could be due to specie differences (human versus dog) since the experimental conditions to determine this parameter were similar in these studies.…”

Section: Discussionmentioning

confidence: 99%

Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer

Sanhueza

Araos

Naranjo

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cancer cells generate protons (H + ) that are extruded to the extracellular medium mainly via the Na + /H + exchanger 1 (NHE1), which regulates intracellular pH (pHi) and cell proliferation. In primary cultures of human ascites-derived ovarian cancer cells (haOC) we assayed whether NHE1 was required for pHi modulation and cell proliferation. Human ovary expresses NHE1, which is higher in haOC and A2780 (ovarian cancer cells) compared with HOSE cells (normal ovarian cells). Basal pHi and pHi recovery (following a NH 4 Cl pulse) was higher in haOC and A2780, compared with HOSE cells. Zoniporide (NHE1 inhibitor) caused intracellular acidification and pHi recovery was independent of intracellular buffer capacity, but reduced in NHE1 knockdown A2780 cells. Zoniporide reduced the maximal proliferation capacity, cell number, thymidine incorporation, and ki67(marker of proliferation) fluorescence in haOC cells. SLC9A1 (for NHE1) amplification associated with lower overall patient survival. In conclusion, NHE1 is expressed in human ovarian cancer where it has a pro-proliferative role. Increased NHE1 expression and activity constitute an unfavourable prognostic factor in these patients.Keywords: NHE1; pHi; human; ovarian cancer; cell proliferation A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT IntroductionOvarian cancer is frequently diagnosed at advanced stages [1,2]. Cancer cells generate protons (H + ) [3], which are released by membrane transport systems resulting in low extracellular pH (pHo), i.e., acidity, but high intracellular pH (pHi), i.e., alkalization [4]. The membrane transport systems involved in pHi control include the sodium (Na + )/H + exchangers (NHEs) [5][6][7][8]. NHE isoform 1 (NHE1) predominates and plays critical roles in cancer [4,[8][9][10]. NHE1 activity causes intracellular alkalization and extracellular acidification [4,11]. Since NHE1 inactivation reduces proliferation of human tumour gastric [12] and small lung cancer [13] cells, NHE1 may act as a pro-proliferative factor in human tumour cells.Mechanisms of pHi control in the human ovary or ascites-cancer cells are unknown [8]. Since non-human ovary cells exhibit NHEs activity [14][15][16][17][18], NHE1 may control the pHi in the human ovary. However, there are not reports addressing expression or activity of NHE1 in human ovarian cancer cells [8]. In this study, we show that functional NHE1 is expressed in human ovarian cancer cells playing a critical role in pHi recovery and cell proliferation. Thus, NHE1 expression and activity are factors that could result in pHidependent modulation of human ovarian cancer cells proliferation. The latter could be relevant to the reduced survival of patients suffering from this disease. Materials and methods Study groupsPatients included in this study (3 patients) coursed with ovarian cancer (high degree of ovarian serous papillary carcinoma stage IIIC or IV, and endometrioid mix type carcinoma with high degree serous differentiation) and were all subjected to primary A C C E P T E ...

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Section: Discussionmentioning

confidence: 99%

Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer

Sanhueza

Araos

Naranjo

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In turn, PDZK1 is required for cAMP-and Ca 2ϩ -dependent NHE3 inhibition (30), and its deletion in rodents results in decreased colonic and jejunal electroneutral sodium absorption (30, 57). NHE2/3 and the NHERF family are important pieces in the pathophysiological puzzle of IBD-associated diarrhea, and as such their roles are presented in Tables 3 and 4. NHE4 is a poorly studied antiporter expressed in healthy human and rat colonic crypts, where, akin to NHE1, it functions as a basolateral intracellular pH regulator (9,16). NHE5 and NHE6 do not seem to be present in the human small intestine or colon (160).…”

Section: Healthy Intestinal Tract Epitheliummentioning

confidence: 99%

Role of epithelial ion transports in inflammatory bowel disease

Magalhães

Cabral

Soares‐da‐Silva

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD patients that results, at least in part, from an intestinal hydroelectrolytic imbalance. Evidence suggests that reduced electrolyte absorption is more relevant than increased secretion to this disequilibrium. This systematic review analyses and integrates the current evidence on the roles of epithelial Na+-K+-ATPase (NKA), Na+/H+ exchangers (NHEs), epithelial Na+ channels (ENaC), and K+ channels (KC) in IBD-associated diarrhea. NKA is the key driving force of the transepithelial ionic transport and its activity is decreased in IBD. In addition, the downregulation of apical NHE and ENaC and the upregulation of apical large-conductance KC all contribute to the IBD-associated diarrhea by lowering sodium absorption and/or increasing potassium secretion.

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“…p < 0.05 was considered statistically significant. [22]. However, there is also evidence that in some intestinal models, culture conditions (e.g., time after seeding or cellular density) may be decisive in determining the expression of NHE isoforms [27].…”

Section: Data Analysis and Statisticsmentioning

confidence: 99%

“…Therefore, the aim of this study was to investigate the putative effects of UGN on some members of the Na + / H + exchanger family (NHEs), as well as to clarify its consequences on transepitelial fluid flow in T84 cells. Although NHE1, NHE2 and NHE4 expression in T84 cells has been reported, their cellular localization and function have not been well established [22]. For this reason, in the present work we first evaluated the functional localization of the different NHE isoforms in T84 polarized cells.…”

Section: Introductionmentioning

confidence: 99%

Uroguanylin Regulates Net Fluid Secretion via the NHE2 Isoform of the Na<sup>+</sup>/H<sup>+</sup> Exchanger in an Intestinal Cellular Model

Toriano

Ozu²,

Politi³

et al. 2011

Cell Physiol Biochem

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Uroguanylin (UGN) has been proposed as a key regulator of salt and water intestinal transport. Uroguanylin activates cell-surface guanylate cyclase C receptor (GC-C) and modulates cellular function via cyclic GMP (cGMP), thus increasing electrolyte and net water secretion. It has been suggested that the action of UGN could involve the Na⁺/H⁺ exchanger, but the actual contribution of this transporter still remains unclear. The objective of our study was to investigate the putative effects of UGN on some members of the Na⁺/H⁺ exchanger family (NHEs), as well as to clarify its consequences on transepithelial fluid flow in T84 cells. In order to do so, transepithelial fluid flow (J_v) was studied by optic techniques and intracellular pH (pH_i) was measured with a fluorescence method. Results showed that NHE2 is found at the apical membrane and has a major role in Na⁺ absorption; NHE1 and NHE4 are localized at the basolateral membrane with a house-keeping role in steady state pH_i. In the assayed conditions, cell exposure to apical UGN increases net secretory J_v, without changing short-circuit currents nor transepithelial resistance, and reduces NHE2 activity. Therefore, at physiological pH, the effect on net J_v was produced mainly by a reduction in normal Na⁺ absorption through NHE2, rather than by the stimulation of electrolyte secretion. Our study shows that the effect of UGN on pH_i is GC-C/cGMP-mediated and enhanced by sildenafil, thus involving PDE5 enzyme. Additionally, cell exposure to apical UGN results in intracellular alkalinization, probably due to indirect effects on basolateral NHE1 and NHE4, which have a major role in pH_i regulation.

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NHE1, NHE2, and NHE4 contribute to regulation of cell pH in T84 colon cancer cells

Cited by 41 publications

References 41 publications

Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer

Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer

Role of epithelial ion transports in inflammatory bowel disease

Uroguanylin Regulates Net Fluid Secretion via the NHE2 Isoform of the Na<sup>+</sup>/H<sup>+</sup> Exchanger in an Intestinal Cellular Model

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