Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Andersen, Anne Poder; Moreira, José M.A.; Pedersen, Stine Falsig

doi:10.1098/rstb.2013.0098

Cited by 95 publications

(77 citation statements)

References 140 publications

(215 reference statements)

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“…Maintenance of alkaline cytosolic pH is thus decisive for the survival of tumor cells [29-31]. Inhibition of Na + /H + exchanger and cytosolic acidification parallels apoptosis [32], whereby cytosolic acidification fosters the activation of caspases [33].…”

Section: Discussionmentioning

confidence: 99%

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells

Abdelazeem

Singh

Läng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Key properties of tumor cells include enhanced glycolytic flux with excessive consumption of glucose and formation of lactate. As glycolysis is highly sensitive to cytosolic pH, maintenance of glycolysis requires export of H⁺ ions, which is in part accomplished by Na⁺/H⁺ exchangers, such as NHE1. The carrier is sensitive to oxidative stress. Growth of tumor cells could be suppressed by the polyphenol Ellagic acid, which is found in various fruits and vegetables. An effect of Ellagic acid on transport processes has, however, never been reported. The present study thus elucidated an effect of Ellagic acid on cytosolic pH (pHi), NHE1 transcript levels, NHE1 protein abundance, Na⁺/H⁺ exchanger activity, and lactate release. Methods: Experiments were performed in Ishikawa cells without or with prior Ellagic acid (20 µM) treatment. NHE1 transcript levels were determined by qRT-PCR, NHE1 protein abundance by Western blotting, pH_i utilizing (2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein [BCECF] fluorescence, Na⁺/H⁺ exchanger activity from Na⁺ dependent realkalinization after an ammonium pulse, cell volume from forward scatter in flow cytometry, reactive oxygen species (ROS) from 2’,7’-dichlorodihydrofluorescein fluorescence, glucose uptake utilizing 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose, and lactate concentration in the supernatant utilizing a colorimetric (570 nm)/ fluorometric enzymatic assay. Results: A 48 hour treatment with Ellagic acid (20 µM) significantly decreased NHE1 transcript levels by 75%, NHE1 protein abundance by 95%, pHi from 7.24 ± 0.01 to 7.02 ± 0.01, Na⁺/H⁺ exchanger activity by 77%, forward scatter by 10%, ROS by 82%, glucose uptake by 58%, and lactate release by 15%. Conclusion: Ellagic acid (20µM) markedly down-regulates ROS formation and NHE1 expression leading to decreased Na⁺/H⁺ exchanger activity, pHi, glucose uptake and lactate release in endometrial cancer cells. Those effects presumably contribute to reprogramming and growth inhibition of tumor cells.

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Section: Discussionmentioning

confidence: 99%

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells

Abdelazeem

Singh

Läng

et al. 2017

Cell Physiol Biochem

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“…(a) pH-dependent regulation of the cytoskeleton in tumour cell migration Intracellular and extracellular pH homeostasis is particularly important in cancer as outlined elsewhere in this issue [4,5,18]. As the ionization state of all cellular and extracellular proteins including their function in ( patho)physiological processes depends on pH, (directional) tumour cell migration is controlled by intra-and extracellular pH [19 -23].…”

Section: Ionic Mechanisms Of Cell Migrationmentioning

confidence: 99%

Ion channels and transporters in tumour cell migration and invasion

Schwab

Stock

2014

Phil. Trans. R. Soc. B

117

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Cell migration is a central component of the metastatic cascade requiring a concerted action of ion channels and transporters (migration-associated transportome), cytoskeletal elements and signalling cascades. Ion transport proteins and aquaporins contribute to tumour cell migration and invasion among other things by inducing local volume changes and/or by modulating Ca 2þ and H þ signalling. Targeting cell migration therapeutically bears great clinical potential, because it is a prerequisite for metastasis. Ion transport proteins appear to be attractive candidate target proteins for this purpose because they are easily accessible as membrane proteins and often overexpressed or activated in cancer. Importantly, a number of clinically widely used drugs are available whose anticipated efficacy as anti-tumour drugs, however, has now only begun to be evaluated.

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“…Dysregulated pH can also affect stromal cells including fibroblasts and endothelial cells (for review see Andersen et al, 2014). Metabolic links between tumor cells and stromal cells are well established (for review see Draoui and Feron, 2011).…”

Section: Box 1 Stromal Cells and Dysregulated Phmentioning

confidence: 99%

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

White

Grillo-Hill

Barber

2017

Journal of Cell Science

289

312

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Dysregulated pH is a common characteristic of cancer cells, as they have an increased intracellular pH ( pH i ) and a decreased extracellular pH ( pH e ) compared with normal cells. Recent work has expanded our knowledge of how dysregulated pH dynamics influences cancer cell behaviors, including proliferation, metastasis, metabolic adaptation and tumorigenesis. Emerging data suggest that the dysregulated pH of cancers enables these specific cell behaviors by altering the structure and function of selective pH-sensitive proteins, termed pH sensors. Recent findings also show that, by blocking pH i increases, cancer cell behaviors can be attenuated. This suggests ion transporter inhibition as an effective therapeutic approach, either singly or in combination with targeted therapies. In this Cell Science at a Glance article and accompanying poster, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression and adaptation.

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Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Cited by 95 publications

References 140 publications

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells

Ion channels and transporters in tumour cell migration and invasion

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

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