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Special Issue "Role of Dysregulation of pH in Cancer"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 30 June 2021.

Special Issue Editor

Prof. Dr. Larry Fliegel
E-Mail Website
Guest Editor
Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, AB T6G 2H7, Canada
Interests: membrane proteins; pH regulation; Na+/H+ exchanger
Special Issues and Collections in MDPI journals

Special Issue Information

Cancer is a daunting multitude of diseases that requires a large variety of therapeutic strategies to treat individual types. Of late, however, evidence has suggested that many types of cancer cells and tumors, and perhaps most kinds, have acid–base disturbances that are opposite to the acid–base distribution in normal tissues, with an interstitial acidosis and intracellular elevated pH. This dysregulation of pH has emerged as a hallmark of cancer. In fact, this phenomenon has been referred to as “a perfect storm” for cancer progression, promoting cell growth, invasion, metastasis, and tumor formation. The abnormalities of intracellular alkalinization together with extracellular acidification in solid tumors and other cells appear to be a specific hallmark of malignancy. Several different proteins are involved in pH regulation and proton gradient reversal. These include the Na+/H+ exchangers NHEs (SLC9A family), the Na+HCO3- cotransporter NBCn1 (SLC4A7), anion exchangers, vacuolar-type adenosine triphosphatases, and the lactate, H+ cotransporters of the monocarboxylate family (MCT1 and MCT4 (SLC16A1 and 3). Additionally, carbonic anhydrases contribute to acid transport. 

This Special Issue on the “Role of Dysregulation of pH in Cancer” invites papers on this topic. It welcomes papers on the phenomenon itself, the proteins involved and contributing to the disease, their regulation in disease development, their contribution to the malignant process, the development of anticancer drugs that affect the process, and their use in the treatment of cancer. Papers on all forms of cancer are of interest.

Prof. Dr. Larry Fliegel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (7 papers)

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Research

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Open AccessArticle
Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells
Int. J. Mol. Sci. 2021, 22(8), 4275; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084275 - 20 Apr 2021
Viewed by 363
Abstract
Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance [...] Read more.
Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1β, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease. Full article
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
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Open AccessArticle
Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors
Int. J. Mol. Sci. 2021, 22(6), 2999; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062999 - 15 Mar 2021
Cited by 1 | Viewed by 420
Abstract
The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, [...] Read more.
The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co-screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition. Full article
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
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Open AccessArticle
Integrin-Linked Kinase Links Integrin Activation to Invadopodia Function and Invasion via the p(T567)-Ezrin/NHERF1/NHE1 Pathway
Int. J. Mol. Sci. 2021, 22(4), 2162; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042162 - 22 Feb 2021
Viewed by 334
Abstract
Tumor cell invasion depends largely on degradation of the extracellular matrix (ECM) by protease-rich structures called invadopodia, whose formation and activity requires the convergence of signaling pathways engaged in cell adhesion, actin assembly, membrane regulation and ECM proteolysis. It is known that β1-integrin [...] Read more.
Tumor cell invasion depends largely on degradation of the extracellular matrix (ECM) by protease-rich structures called invadopodia, whose formation and activity requires the convergence of signaling pathways engaged in cell adhesion, actin assembly, membrane regulation and ECM proteolysis. It is known that β1-integrin stimulates invadopodia function through an invadopodial p(T567)-ezrin/NHERF1/NHE1 signal complex that regulates NHE1-driven invadopodia proteolytic activity and invasion. However, the link between β1-integrin and this signaling complex is unknown. In this study, in metastatic breast (MDA-MB-231) and prostate (PC-3) cancer cells, we report that integrin-linked kinase (ILK) integrates β1-integrin with this signaling complex to regulate invadopodia activity and invasion. Proximity ligation assay experiments demonstrate that, in invadopodia, ILK associates with β1-integrin, NHE1 and the scaffold proteins p(T567)-ezrin and NHERF1. Activation of β1-integrin increased both invasion and invadopodia activity, which were specifically blocked by inhibition of either NHE1 or ILK. We conclude that ILK integrates β1-integrin with the ECM proteolytic/invasion signal module to induce NHE1-driven invadopodial ECM proteolysis and cell invasion. Full article
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
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Review

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Open AccessReview
Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases
Int. J. Mol. Sci. 2021, 22(6), 3171; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063171 - 20 Mar 2021
Viewed by 347
Abstract
Intra- and extracellular pH regulation is a pivotal function of all cells and tissues. Net outward transport of H+ is a prerequisite for normal physiological function, since a number of intracellular processes, such as metabolism and energy supply, produce acid. In tumor [...] Read more.
Intra- and extracellular pH regulation is a pivotal function of all cells and tissues. Net outward transport of H+ is a prerequisite for normal physiological function, since a number of intracellular processes, such as metabolism and energy supply, produce acid. In tumor tissues, distorted pH regulation results in extracellular acidification and the formation of a hostile environment in which cancer cells can outcompete healthy local host cells. Cancer cells employ a variety of H+/HCO3-coupled transporters in combination with intra- and extracellular carbonic anhydrase (CA) isoforms, to alter intra- and extracellular pH to values that promote tumor progression. Many of the transporters could closely associate to CAs, to form a protein complex coined “transport metabolon”. While transport metabolons built with HCO3-coupled transporters require CA catalytic activity, transport metabolons with monocarboxylate transporters (MCTs) operate independently from CA catalytic function. In this article, we assess some of the processes and functions of CAs for tumor pH regulation and discuss the role of intra- and extracellular pH regulation for cancer pathogenesis and therapeutic intervention. Full article
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
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Open AccessReview
Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity
Int. J. Mol. Sci. 2020, 21(21), 8363; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218363 - 07 Nov 2020
Cited by 5 | Viewed by 798
Abstract
Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid [...] Read more.
Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although lactic acid has long been considered a waste product of this alteration, it is now well accepted that increased lactic acid production and the resultant acidification of the tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, and drug resistance. We and others have hypothesized that excess lactic acid in the TME is responsible for suppressing anticancer immunity. Recent studies support this hypothesis and provide mechanistic evidence explaining how lactic acid and the acidic TME impede immune cell functions. In this review, we consider lactic acid’s role as a critical immunoregulatory molecule involved in suppressing immune effector cell proliferation and inducing immune cell de-differentiation. This results in the inhibition of antitumor immune responses and the activation of potent, negative regulators of innate and adaptive immune cells. We also consider the role of an acidic TME in suppressing anticancer immunity. Finally, we provide insights to help translate this new knowledge into impactful anticancer immune therapies. Full article
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
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Open AccessReview
Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era
Int. J. Mol. Sci. 2020, 21(20), 7475; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207475 - 10 Oct 2020
Viewed by 765
Abstract
A brand new approach to the understanding of breast cancer (BC) is urgently needed. In this contribution, the etiology, pathogenesis, and treatment of this disease is approached from the new pH-centric anticancer paradigm. Only this unitarian perspective, based upon the hydrogen ion (H [...] Read more.
A brand new approach to the understanding of breast cancer (BC) is urgently needed. In this contribution, the etiology, pathogenesis, and treatment of this disease is approached from the new pH-centric anticancer paradigm. Only this unitarian perspective, based upon the hydrogen ion (H+) dynamics of cancer, allows for the understanding and integration of the many dualisms, confusions, and paradoxes of the disease. The new H+-related, wide-ranging model can embrace, from a unique perspective, the many aspects of the disease and, at the same time, therapeutically interfere with most, if not all, of the hallmarks of cancer known to date. The pH-related armamentarium available for the treatment of BC reviewed here may be beneficial for all types and stages of the disease. In this vein, we have attempted a megasynthesis of traditional and new knowledge in the different areas of breast cancer research and treatment based upon the wide-ranging approach afforded by the hydrogen ion dynamics of cancer. The concerted utilization of the pH-related drugs that are available nowadays for the treatment of breast cancer is advanced. Full article
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
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Other

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Open AccessCase Report
Targeting the pH Paradigm at the Bedside: A Practical Approach
Int. J. Mol. Sci. 2020, 21(23), 9221; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239221 - 03 Dec 2020
Cited by 1 | Viewed by 603
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
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