The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

Lee, Dong‐Un; Hong, Jeong Hee

doi:10.3390/ijms21010339

Cited by 39 publications

(29 citation statements)

References 142 publications

(193 reference statements)

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“…These transporters are of particular interest in cancer research because CO 2 -dependent acid production from high metabolism and excessive glycolysis corresponds to approximately half of the extracellular acids that cancer cells generate (13). Studies on cultured cancer cells in vitro or implanted in vivo have identified NBC-mediated acid extrusion mechanisms in a variety of cancer cells and their involvement in cell growth and progression (2,14). Notably, NBCn1/SLC4A7 was identified as a new marker for human breast cancer (15) and its contribution to cancer progression has been recognized in MCF17 breast cancer cells (16,17) and breast cancer cells from patients (18).…”

Section: Introductionmentioning

confidence: 99%

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

Lee

Zafar

et al. 2021

Oncol Rep

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Studies on cultured cancer cells or cell lines have revealed multiple acid extrusion mechanisms and their involvement in cancer cell growth and progression. In the present study, the role of the sodium bicarbonate transporters (NBCs) in prostate cancer cell proliferation and viability was examined. qPCR revealed heterogeneous expression of five NBC isoforms in human prostate cancer cell lines LNCaP, PC3, 22RV1, C4-2, DU145, and the prostate cell line RWPE-1. In fluorescence pH measurement of LNCaP cells, which predominantly express NBCe1, Na + and HCO 3 --mediated acid extrusion was identified by bath ion replacement and sensitivity to the NBC inhibitor S0859. NBCe1 knockdown using siRNA oligonucleotides decreased the number of viable cells, and pharmacological inhibition with S0859 (50 µM) resulted in a similar decrease. NBCe1 knockdown and inhibition also increased cell death, but this effect was small and slow. In PC3 cells, which express all NBC isoforms, NBCe1 knockdown decreased viable cell number and increased cell death. The effects of NBCe1 knockdown were comparable to those by S0859, indicating that NBCe1 among NBCs primarily contributes to PC3 cell proliferation and viability. S0859 inhibition also decreased the formation of cell spheres in 3D cultures. Immunohistochemistry of human prostate cancer tissue microarrays revealed NBCe1 localization to the glandular epithelial cells in prostate tissue and robust expression in acinar and duct adenocarcinoma. In conclusion, our study demonstrates that NBCe1 regulates acid extrusion in prostate cancer cells and inhibiting or abolishing this transporter decreases cancer cell proliferation.

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Section: Introductionmentioning

confidence: 99%

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

Lee

Zafar

et al. 2021

Oncol Rep

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“…CAs are an important family of enzymes that catalyze the conversion of CO 2 into HCO 3 − to regulate the pH balance of the blood. [37][38][39].…”

Section: Comparison Of Gene Expression Levels Of Control and Mutant Gmentioning

confidence: 99%

Tip60 Might Be a Candidate For The Acetylation of Hepatic Carbonic Anhydrase I and III in Mice

BALTACI

Koçpınar

Budak

2021

Preprint

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Carbonic anhydrases (CAs) play an important role in maintaining pH balance by catalyzing the conversion of carbon dioxide to bicarbonate. Since this pH balance is critical to health, all organisms must develop mechanisms to control and regulate it. Although there is a great deal of literature on the biochemical, functional, and structural properties of the CA family, there is no enough knowledge on the regulation of CAs at gene and protein levels, especially their epigenetic regulation. In this study, impact of Tip60, a member of histone acetyltransferases family, on the expression of Ca1 and Ca3 genes in liver tissue was investigated at different zeitgeber time points in control and liver-specific Tip60 knockout mice (mutant) groups. First of all, Tip60 was specifically knocked out in mouse liver the using Cre/loxP system and knockout rate was shown as 83% - 88% by southern blot. Expression profiles of Ca1 and Ca3 genes in both groups were determined by Real-Time PCR at six different time points. While Ca1 showed the highest expression at ZT8 and ZT12, the lowest expression profile was observed at ZT0 and ZT20. Hepatic Ca1 showed a robust circadian expression. While hepatic Ca3 showed almost the same level of expression at different time units. The expression of Ca1 and Ca3 significantly decreased in the absence of Tip60 in mouse liver all time period. In conclusion, it was suggested for the first time that Tip60 may be considered a candidate protein in the regulation of Ca1 and Ca3 genes, possibly by acetylation.

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“…CAs work "in tandem" with NBC1 [65] that introduces the bicarbonate produced by the CAs into the cell. The "coordinator" of this tandem work is in the hands of membrane carbonic anhydrases that regulate the amount of bicarbonate produced and at the same time, participate in the bicarbonate transport process [66,67].…”

Section: The Phtome and How The Paradigm Appearsmentioning

confidence: 99%

Targeting the pH Paradigm at the Bedside: A Practical Approach

Koltai¹

2020

IJMS

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The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the “cancer problem”? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article’s goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.

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The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

Cited by 39 publications

References 142 publications

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

Tip60 Might Be a Candidate For The Acetylation of Hepatic Carbonic Anhydrase I and III in Mice

Targeting the pH Paradigm at the Bedside: A Practical Approach

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