Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

Journal of Cell Science, Journal Year: 2017, Volume and Issue: 130(4), P. 663 - 669

Published: Feb. 15, 2017

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

Language: Английский

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Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters

Journal of Molecular Medicine, Journal Year: 2015, Volume and Issue: 94(2), P. 155 - 171

Published: June 23, 2015

Since Otto Warburg reported the 'addiction' of cancer cells to fermentative glycolysis, a metabolic pathway that provides energy and building blocks, thousands studies have shed new light on molecular mechanisms contributing altered metabolism. Hypoxia, through hypoxia-inducible factors (HIFs), in addition oncogenes activation loss tumour suppressors constitute major regulators not only "Warburg effect" but also many other pathways such as glutaminolysis. Enhanced glucose glutamine catabolism has become recognised feature cells, leading accumulation metabolites microenvironment, which offers growth advantages tumours. Among these metabolites, lactic acid, besides imposing an acidic stress, is emerging key signalling molecule plays pivotal role cell migration, angiogenesis, immune escape metastasis. Although interest lactate for development appeared recently, pharmacological molecules blocking its metabolism are already phase I/II clinical trials. Here, we review generating lactate, discuss rationale targeting acid transporter complexes efficient selective anticancer therapies.

Language: Английский

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Carbonic anhydrase IX and acid transport in cancer

British Journal of Cancer, Journal Year: 2019, Volume and Issue: 122(2), P. 157 - 167

Published: Dec. 10, 2019

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

Language: Английский

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Tumor pH and metastasis: a malignant process beyond hypoxia

Cancer and Metastasis Reviews, Journal Year: 2019, Volume and Issue: 38(1-2), P. 113 - 129

Published: Jan. 3, 2019

Language: Английский

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Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(12), P. 1464 - 1483

Published: Dec. 15, 2022

Solid tumors are generally characterized by an acidic tumor microenvironment (TME) that favors cancer progression, therapy resistance and immune evasion. By single-cell RNA-sequencing analysis in individuals with pancreatic ductal adenocarcinoma (PDAC), we reveal solute carrier family 4 member (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed epithelial cells. Functionally, SLC4A4 inhibition PDAC cells mitigates acidosis of TME due to accumulation extracellular space a decrease lactate production result reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological targeting improves T cell-mediated response breaches macrophage-mediated immunosuppression, thus inhibiting growth metastases. addition, Slc4a4 combination checkpoint blockade is able overcome immunotherapy prolong survival. Overall, our data propose therapeutic target unleash antitumor PDAC.

Language: Английский

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Hypoxia and cellular metabolism in tumour pathophysiology

The Journal of Physiology, Journal Year: 2017, Volume and Issue: 595(8), P. 2439 - 2450

Published: Jan. 11, 2017

Abstract Cancer cells are optimised for growth and survival via an ability to outcompete normal in their microenvironment. Many of these advantageous cellular adaptations promoted by the pathophysiological hypoxia that arises solid tumours due incomplete vascularisation. Tumour thus faced with challenge increased need nutrients support drive proliferation face a diminished extracellular supply. Among many modifications occurring tumour cells, inducible factors (HIFs) act as essential drivers key pro‐survival pathways promotion numerous membrane cytosolic proteins. Here we focus our attention on two areas: role amino acid uptake handling metabolic (CO 2 /H + ) production. We provide evidence number hypoxia‐induced proteins promote anabolism regulation acid–base levels including amino‐acid transporters (LAT1), monocarboxylate transporters, regulating carbonic anhydrases (CAs) bicarbonate (NBCs). Emphasis is placed current work manipulating multiple CA isoforms NBCs, which at interesting crossroads gas physiology they regulated contribute CO pH i regulation. Our research combined others indicates targeting HIF‐regulated will promising future anti‐cancer therapeutic approaches suggest strategies could be potentially used enhance tactics. image

Language: Английский

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The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion

Oncogene, Journal Year: 2017, Volume and Issue: 36(45), P. 6244 - 6261

Published: July 10, 2017

Carbonic anhydrase IX (CAIX) is a hypoxia inducible factor 1-induced, cell surface pH regulating enzyme with an established role in tumor progression and clinical outcome. However, the molecular basis of CAIX-mediated remains unclear. Here, we have utilized proximity dependent biotinylation (BioID) to map CAIX 'interactome' breast cancer cells order identify physiologically relevant CAIX-associating proteins potential roles progression. High confidence identified include metabolic transporters, β1 integrins, integrin-associated protein CD98hc matrix metalloprotease 14 (MMP14). Biochemical studies validate association α2β1 integrin, MMP14, immunofluorescence microscopy demonstrates colocalization integrin MMP14 F-actin/cofilin-positive lamellipodia/pseudopodia, cortactin/Tks5-positive invadopodia. Modulation expression activity results significant changes migration, collagen degradation invasion. Mechanistically, demonstrate that associates through phosphorylation residues within its intracellular domain, enhances MMP14-mediated by directly contributing hydrogen ions required for catalytic activity. These findings establish hypoxia-induced as novel component cellular migration invasion structures, provide new mechanistic insights into biology.

Language: Английский

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Cancer: fundamentals behind pH targeting and the double-edged approach

OncoTargets and Therapy, Journal Year: 2016, Volume and Issue: Volume 9, P. 6343 - 6360

Published: Oct. 1, 2016

Abstract: The highly regulated pH of cells and the less-regulated surrounding extracellular matrix (ECM) is result a delicate balance between metabolic processes proton production, transportation, chemical buffering, vascular removal waste products. Malignant show pronounced increase in where 10- to 15-fold rise glucose consumption only tip iceberg. Aerobic glycolysis (Warburg effect) one hallmarks cancer metabolism that implies excessive production protons, which if stayed inside would fatal intracellular acidosis (maintaining strict acid–base essential for survival eukaryotic cells). solve this problem by increasing mechanisms transportation expel excess acidity. This allows keep normal pH, or even overshooting mechanism permits slightly alkaline tendency. expelled from malignant accumulates ECM, chronic hypoxia relative lack enough blood vessels impede adequate clearance, thus creating an acidic microenvironment. microenvironment quite heterogeneous due tumor’s heterogeneity variable degrees tumor mass. environment (plus other necessary cellular modifications) stimulates migration invasion finally intravasation eventually may metastasis. Targeting go two directions: 1) should less migration, invasion, metastasis; 2) decreasing stress apoptosis. Both objectives seem achievable at present state art with repurposed drugs. hypothesis analyzes altered tumors its implications progression metastasis also possible drug combinations targeting vulnerable side development. It double-edged approach, consists pharmacologically simultaneously extrusion acidity, acid stress, eventual Keywords: processes, cells, acid, apoptosis, Warburg effect

Language: Английский

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Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

Cancer Research, Journal Year: 2016, Volume and Issue: 76(13), P. 3744 - 3755

Published: May 18, 2016

Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor activated expression carbonic anhydrase IX (CA9), a regulator pH growth. In this study, we investigated the hypothesis that impeding reuptake bicarbonate produced extracellularly by CA9 could exacerbate intracellular acidity hypoxic conditions, perhaps compromising cell growth viability as result. 8 10 cancer lines, found induced at least one transporter. The most robust frequent inductions were sodium-driven transporters SLC4A4 SLC4A9, which rely upon both HIF1α HIF2α activity for their expression. spheroids, or SLC4A9 disruption either genetic pharmaceutical approaches acidified reduced Furthermore, treatment spheroids S0859, small-molecule inhibitor transporters, increased apoptosis in lines tested. Finally, RNAi-mediated attenuation MDA-MB-231 breast dramatically tumors U87 gliomas murine xenografts. Our findings suggest disrupting homeostasis blocking import might broadly relieve common to anticancer therapy. Cancer Res; 76(13); 3744-55. ©2016 AACR.

Language: Английский

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MiR-223-3p promotes cell proliferation and metastasis by downregulating SLC4A4 in clear cell renal cell carcinoma

Aging, Journal Year: 2019, Volume and Issue: 11(2), P. 615 - 633

Published: Jan. 22, 2019

MicroRNAs (miRNAs) are known to affect the occurrence and progression of cancer. We therefore evaluated involvement miR-223-3p in renal cell MiR-223-3p was highly expressed clear cancer tissues. Clear patients with higher expression had tumor stages grades poorer prognoses. In cells, overexpression enhanced proliferation metastasis, while inhibition reduced malignant capacity cells. found bind directly solute carrier family 4, member 4 (SLC4A4) mRNA, thereby reducing SLC4A4 mRNA protein expression. restrained metastasis by suppressing Kirsten rat sarcoma viral oncogene (KRAS) correlated negatively patient samples. Given that suppressed SLC4A4/KRAS axis, gene therapy could be an effective treatment for

Language: Английский

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