scholarly journals Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases

2021 ◽  
Vol 22 (6) ◽  
pp. 3171
Author(s):  
Holger M. Becker ◽  
Joachim W. Deitmer
Keyword(s):  
Cancer Cells ◽  
Ph Regulation ◽  
Extracellular Ph ◽  
Host Cells ◽  
Carbonic Anhydrases ◽  
Catalytic Function ◽  
Tumor Ph ◽  
Cancer Pathogenesis ◽  
Outward Transport

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.

scholarly journals Transport Metabolons and Acid/Base Balance in Tumor Cells

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 899 ◽  
Author(s):  
Holger M. Becker ◽  
Joachim W. Deitmer
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Drug Targets ◽  
Ph Regulation ◽  
Host Cells ◽  
Bicarbonate Transport ◽  
Carbonic Anhydrases ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance

Solid tumors are metabolically highly active tissues, which produce large amounts of acid. The acid/base balance in tumor cells is regulated by the concerted interplay between a variety of membrane transporters and carbonic anhydrases (CAs), which cooperate to produce an alkaline intracellular, and an acidic extracellular, environment, in which cancer cells can outcompete their adjacent host cells. Many acid/base transporters form a structural and functional complex with CAs, coined “transport metabolon”. Transport metabolons with bicarbonate transporters require the binding of CA to the transporter and CA enzymatic activity. In cancer cells, these bicarbonate transport metabolons have been attributed a role in pH regulation and cell migration. Another type of transport metabolon is formed between CAs and monocarboxylate transporters, which mediate proton-coupled lactate transport across the cell membrane. In this complex, CAs function as “proton antenna” for the transporter, which mediate the rapid exchange of protons between the transporter and the surroundings. These transport metabolons do not require CA catalytic activity, and support the rapid efflux of lactate and protons from hypoxic cancer cells to allow sustained glycolytic activity and cell proliferation. Due to their prominent role in tumor acid/base regulation and metabolism, transport metabolons might be promising drug targets for new approaches in cancer therapy.

scholarly journals Role of acidic tumor microenvironment in tumor pathogenesis and targeting

2020 ◽  
pp. 34-40
Author(s):  
Vishal Sharma ◽  
Chhaya Bawa ◽  
Kuldeep Chand Vatsyan
Keyword(s):  
Cell Growth ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Physiological State ◽  
Therapeutic Interventions ◽  
Cancer Cell Growth ◽  
Molecular Alterations ◽  
Cancer Pathogenesis

Extensive efforts are going on to understand the molecular mechanisms behind tumor initiation, progression, and invasion and find novel targets for cancer treatment. The physiological state of the tumor microenvironment (TME) is crucial to every step of tumor cell growth and angiogenesis. Cancer cells are rarely in contact with each other. The intervening medium between the cancer cells, immune cells, and other cells become acidic, which significantly affects cancer pathogenesis. It could be a novel targeting marker and may help treat tumors. Even after extensive research in this area, the nature of molecular alterations and the basic mechanisms in the tumor microenvironment remains unclear. Based on recent studies of TME, this mini-review bids a more inclusive overview of the role of TME in cancer cell growth. Also, it helps to understand the potential of TME for therapeutic interventions.

scholarly journals Role of Carbonic Anhydrases and Inhibitors in Acid–Base Physiology: Insights from Mathematical Modeling

2019 ◽  
Vol 20 (15) ◽  
pp. 3841 ◽  
Author(s):  
Occhipinti ◽  
Boron
Keyword(s):  
Mathematical Modeling ◽  
Ph Regulation ◽  
Reaction Diffusion ◽  
The Body ◽  
Whole Body ◽  
Facilitated Diffusion ◽  
Carbonic Anhydrases ◽  
Physiological Processes ◽  
Urinary Acid

Carbonic anhydrases (CAs) catalyze a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO2) and water (H2O) into bicarbonate (HCO3−) and protons (H+). These enzymes impact numerous physiological processes that occur within and across the many compartments in the body. Within compartments, CAs promote rapid H+ buffering and thus the stability of pH-sensitive processes. Between compartments, CAs promote movements of H+, CO2, HCO3−, and related species. This traffic is central to respiration, digestion, and whole-body/cellular pH regulation. Here, we focus on the role of mathematical modeling in understanding how CA enhances buffering as well as gradients that drive fluxes of CO2 and other solutes (facilitated diffusion). We also examine urinary acid secretion and the carriage of CO2 by the respiratory system. We propose that the broad physiological impact of CAs stem from three fundamental actions: promoting H+ buffering, enhancing H+ exchange between buffer systems, and facilitating diffusion. Mathematical modeling can be a powerful tool for: (1) clarifying the complex interdependencies among reaction, diffusion, and protein-mediated components of physiological processes; (2) formulating hypotheses and making predictions to be tested in wet-lab experiments; and (3) inferring data that are impossible to measure.

scholarly journals Importance of Biometals as Targets in Medicinal Chemistry: An Overview about the Role of Zinc (II) Chelating Agents

2020 ◽  
Vol 10 (12) ◽  
pp. 4118
Author(s):  
Rosalba Leuci ◽  
Leonardo Brunetti ◽  
Antonio Laghezza ◽  
Fulvio Loiodice ◽  
Paolo Tortorella ◽  
...  
Keyword(s):  
Human Physiology ◽  
Side Effects ◽  
Matrix Metalloproteinases ◽  
Medicinal Chemistry ◽  
Chelating Agents ◽  
Carbonic Anhydrases ◽  
Catalytic Function ◽  
Chemistry Research ◽  
Important Target

Zinc (II) is an important biometal in human physiology. Moreover, in the last two decades, it was deeply studied for its involvement in several pathological states. In particular, the regulation of its concentration in synaptic clefts can be fundamental for the treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Zinc (II) is also a constituent of metalloenzymes (i.e., matrix metalloproteinases, MMPs, and carbonic anhydrases, CAs) with catalytic function; therefore, it can be an important target for the inhibition of these proteins, frequently involved in cancer onset. This review is focused on the significance of zinc (II) chelating agents in past and future medicinal chemistry research, and on the importance of selectivity in order to revamp the possibility of their use in therapy, often hindered by possible side effects.

scholarly journals The Role of Epidermal Growth Factor Receptor in Cancer Metastasis and Microenvironment

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Takamitsu Sasaki ◽  
Kuniyasu Hiroki ◽  
Yuichi Yamashita
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Surgical Techniques ◽  
Growth Factor Receptor ◽  
Host Cells ◽  
Colon Cancer Cells ◽  
Egfr Signaling ◽  
Epidermal Growth ◽  
Multiple Interactions

Despite significant improvements in diagnosis, surgical techniques, and advancements in general patient care, the majority of deaths from cancer are caused by the metastases. There is an urgent need for an improved understanding of the cellular and molecular factors that promote cancer metastasis. The process of cancer metastasis depends on multiple interactions between cancer cells and host cells. Studies investigating the TGFα-EGFR signaling pathways that promote the growth and spread of cancer cells. Moreover, the signaling activates not only tumor cells, but also tumor-associated endothelial cells. TGFα-EGFR signaling in colon cancer cells creates a microenvironment that is conducive for metastasis, providing a rationale for efforts to inhibit EGFR signaling in TGFα-positive cancers. In this review, we describe the recent advances in our understanding of the molecular basis of cancer metastasis.

scholarly journals Selective inhibition of CA IX over CA XII in breast cancer cells using benzene sulfonamides: Disconnect between CA activity and growth inhibition

2018 ◽  
Author(s):  
Mam Y. Mboge ◽  
Zhijuan Chen ◽  
Alyssa Wolff ◽  
John V. Mathias ◽  
Chingkuang Tu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Active Site ◽  
Breast Cancer Cells ◽  
Cell Types ◽  
Chemotherapeutic Agents ◽  
Carbonic Anhydrases ◽  
Ca Ix

AbstractCarbonic anhydrases (CAs) have been linked to tumor progression, particularly membrane-bound CA isoform IX (CA IX). The role of CA IX in the context of breast cancer is to regulate the pH of the tumor microenvironment. In contrast to CA IX, expression of CA XII, specifically in breast cancer, is associated with better outcome despite performing the same catalytic function. In this study, we have structurally modeled the orientation of bound ureido-substituted benzene sulfonamides (USBs) within the active site of CA XII, in comparison to CA IX and cytosolic off-target CA II, to understand isoform specific inhibition. This has identified specific residues within the CA active site, which differ between isoforms that are important for inhibitor binding and isoform specificity. The ability of these sulfonamides to block CA IX activity in breast cancer cells is less effective than their ability to block activity of the recombinant protein (by one to two orders of magnitude depending on the inhibitor). The same is true for CA XII activity but now they are two to three orders of magnitude less effective. Thus, there is significantly greater specificity for CA IX activity over CA XII. While the inhibitors block cell growth, without inducing cell death, this again occurs at two orders of magnitude above the Kivalues for inhibition of CA IX and CA XII activity in their respective cell types. Surprisingly, the USBs inhibited cell growth even in cells where CA IX and CA XII expression was ablated. Despite the potential for these sulfonamides as chemotherapeutic agents, these data suggest that we reconsider the role of CA activity on growth potentiation.

scholarly journals Carbonic anhydrase IX and acid transport in cancer

2019 ◽  
Vol 122 (2) ◽  
pp. 157-167 ◽  
Author(s):  
Holger M. Becker
Keyword(s):  
Cancer Cells ◽  
Ph Regulation ◽  
Migration And Invasion ◽  
Carbonic Anhydrases ◽  
Hostile Environment ◽  
Proton Extrusion ◽  
Acid Base ◽  
Current State ◽  
Bicarbonate Transporters ◽  
State Of Research

AbstractAlterations in tumour metabolism and acid/base regulation result in the formation of a hostile environment, which fosters tumour growth and metastasis. Acid/base homoeostasis in cancer cells is governed by the concerted interplay between carbonic anhydrases (CAs) and various transport proteins, which either mediate proton extrusion or the shuttling of acid/base equivalents, such as bicarbonate and lactate, across the cell membrane. Accumulating evidence suggests that some of these transporters interact both directly and functionally with CAIX to form a protein complex coined the ‘transport metabolon’. Transport metabolons formed between bicarbonate transporters and CAIX require CA catalytic activity and have a function in cancer cell migration and invasion. Another type of transport metabolon is formed by CAIX and monocarboxylate transporters. In this complex, CAIX functions as a proton antenna for the transporter, which drives the export of lactate and protons from the cell. Since CAIX is almost exclusively expressed in cancer cells, these transport metabolons might serve as promising targets to interfere with tumour pH regulation and energy metabolism. This review provides an overview of the current state of research on the function of CAIX in tumour acid/base transport and discusses how CAIX transport metabolons could be exploited in modern cancer therapy.

792: Role of Oxidative Stress in Tumorigenic Potential of Bladder Cancer Cells

2005 ◽  
Vol 173 (4S) ◽  
pp. 214-215 ◽  
Author(s):  
Daniel Cho ◽  
Xiao Fang Ha ◽  
J. Andre Melendez ◽  
Louis J. Giorgi ◽  
Badar M. Mian
Keyword(s):  
Oxidative Stress ◽  
Bladder Cancer ◽  
Cancer Cells ◽  
Tumorigenic Potential ◽  
Bladder Cancer Cells

Role of exosomes in diagnosis and therapy of prostate cancer

2020 ◽  
Vol 28 (3) ◽  
pp. 399-405
Author(s):  
Fabrizio Fontana ◽  
Olga A. Babenko
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Biological Fluids ◽  
Diagnosis And Treatment ◽  
Diagnosis And Therapy ◽  
The Future ◽  
Important Direction ◽  
Potential Biomarkers

Aim of this letter is to attract the attention of journal readers to the study of exosomes as an important direction in the development of Oncology, in particular, in the diagnosis and treatment of prostate cancer. Exosomes are produced by tumor cells and regulate proliferation, metastasis, and the development of chemoresistance. Their extraction from biological fluids allows further use of these vesicles as potential biomarkers of prostate cancer. In the future, exosomes can be successfully used in the delivery of drugs and other anti-tumor substances to cancer cells.

Sign in / Sign up

Export Citation Format

Share Document