Defining the Na+/H+ exchanger NHE1 interactome in triple-negative breast cancer cells

Amith, Schammim Ray; Vincent, Krista; Wilkinson, Jodi Marie; Postovit, Lynne-Marie; Fliegel, Larry

doi:10.1016/j.cellsig.2016.10.005

Cited by 23 publications

(22 citation statements)

References 70 publications

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“…However, when this database was reanalysed for tumour subtype, luminal A (N=421), luminal B (N=192), and HER2-amplified (N=67) tumours did not show a difference in NHE1 mRNA expression compared to normal associated breast tissue (N=23). Intriguingly, NHE1 mRNA expression in basal breast tumours (N=141) was significantly lower than in normal breast tissue (82). This trend is comparable to the NHE1 protein expression we observed in luminal A MCF-7 cells, which expressed higher levels of NHE1 protein, but had lower metastatic capacity, compared to basal-like, triple-negative MDA-MB-231 and MDA-MB-468 cells (71).…”

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negasupporting

confidence: 68%

“…We suggest it is the activity of the protein, and not its amount per se, that is critical. In this regard, we found that active (phosphorylated) p90 RSK , which regulates NHE1 by phosphorylation of serine 703, was positively correlated with NHE1 in some triple-negative tumour types (82). Further studies in the area could examine the correlation between NHE1 regulation and metastatic behaviour.…”

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negamentioning

confidence: 94%

“…Interestingly, 14-3-3 is also known to bind phospho-vimentin, and it is important in the dephosphorylation and disaggregation of vimentin (81). We have not yet been able to demonstrate a direct association between NHE1 and vimentin, but we have shown that several isoforms of 14-3-3 bind to and co-immunoprecipitate with NHE1 (82). Whether and how 14-3-3 links NHE1 to the vimentin intermediate filament cytoskeleton remains unclear.…”

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negamentioning

confidence: 96%

“…In another study, we used bioinformatics to assess gene profiles of primary patient breast tumours using the Cancer Genome Atlas (82). We found that NHE1 mRNA expression in primary breast tumours (N=1062) was significantly higher compared to normal associated breast tissue (N=113).…”

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negamentioning

confidence: 99%

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Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

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Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negasupporting

confidence: 68%

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negamentioning

confidence: 94%

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negamentioning

confidence: 96%

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negamentioning

confidence: 99%

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Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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“…Taking into account those data, it is then difficult for us to explain the link between NHE1 and HKII via the mere increase in pH i . As NHE1 is also known as capable of forming protein complex for intracellular signaling [47,68,69], one might then suggest the existence of such a complex that would comprise NHE1, GSK3α and p53, all necessary for c-Myc down-regulation [59]. In this context, it would be interesting to analyze the NHE1 interactome under B[a]P exposure.…”

Section: -2-1-nhe1 and Hexokinase IImentioning

confidence: 99%

Disturbances in H+ dynamics during environmental carcinogenesis

et al. 2019

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Abbreviations: B[a]P: benzo[a]pyrene; GPCR: G-protein coupled receptor; MCT: monocarboxylate transporter; NHE1: Na + /H + exchanger 1HIGHLIGHTS Benzo[a]pyrene, a well-known environmental carcinogen, alters H + dynamics. NHE1 activation by B[a]P plays a key role in H + dynamics alterations. B[a]P-altered pH controls cell death/survival balance via mitochondria and lysosome. ABSTRACTDespite the improvement of diagnostic methods and anticancer therapeutics, the human population is still facing an increasing incidence of several types of cancers. According to the World Health Organization, this growing trend would be partly linked to our environment, with around 20% of cancers stemming from exposure to environmental contaminants, notably chemicals like polycyclic aromatic hydrocarbons (PAHs). PAHs are widespread pollutants in our environment resulting from incomplete combustion or pyrolysis of organic material, and thus produced by both natural and anthropic sources; notably benzo[a]pyrene (B[a]P), i.e. the prototypical molecule of this family, that can be detected in cigarette smoke, diesel exhaust particles, occupational-related fumes, and grilled food. This molecule is a well-recognized carcinogen belonging to group 1 carcinogens. Indeed, it can target the different steps of the carcinogenic process and all cancer hallmarks. Interestingly, H + dynamics have been described as key parameters for the occurrence of several, if not all, of these hallmarks. However, information regarding the role of such parameters during environmental carcinogenesis is still very scarce. The present review will thus mainly give an overview of the impact of B[a]P on H + dynamics in liver cells, and will show how such alterations might impact different aspects related to the finely-tuned balance between cell death and survival processes, thereby likely favoring environmental carcinogenesis. In total, the main objective of this review is to encourage further research in this poorly explored field of environmental molecular toxicology.

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Differential expression of the long and truncated Hv1 isoforms in breast‐cancer cells

Ventura

León

Asuaje

et al. 2020

Journal Cellular Physiology

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Metabolic reprogramming of cancer cells results in a high production of acidic substances that must be extruded to maintain tumor‐cell viability. The voltage‐gated proton channel (Hv1) mediates highly selective effluxes of hydronium‐ion (H+) that prevent deleterious cytoplasmic acidification. In the work described here, we demonstrated for the first time that the amino‐terminal–truncated isoform of Hv1 is more highly expressed in tumorigenic breast‐cancer‐cell lines than in nontumorigenic breast cells. With respect to Hv1 function, we observed that pharmacologic inhibition of that channel, mediated by the specific blocker 5‐chloro‐2‐guanidinobenzimidazole, produced a drop in intracellular pH and a decrease in cell viability, both in monolayer and in three‐dimensional cultures, and adversely affected the cell‐cycle in tumorigenic breast cells without altering the cycling of nontumorigenic cells. In conclusion, our results demonstrated that the Hv1 channel could be a potential tool both as a biomarker and as a therapeutic target in breast‐cancer disease.

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Defining the Na+/H+ exchanger NHE1 interactome in triple-negative breast cancer cells

Cited by 23 publications

References 70 publications

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Disturbances in H+ dynamics during environmental carcinogenesis

Differential expression of the long and truncated Hv1 isoforms in breast‐cancer cells

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