Modeling of pH regulation in tumor cells: Direct interaction between proton-coupled lactate transporters and cancer-associated carbonicanhydrase

Hiremath, Sandesh Athni; Surulescu, Christina; Jamali, Somayeh; Ames, Samantha; Deitmer, Joachim W.; Becker, Holger M.

doi:10.3934/mbe.2019016

Cited by 9 publications

(15 citation statements)

References 37 publications

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“…We have developed a biophysical model to explore the complex molecular mechanisms that allow tumor cells to regulate both intracellular and extracellular acidity, but we are not alone, other modeling efforts have tried to capture the essential features of the biochemical pathways that lead to acid homeostasis in tumor cells (see e.g. (30)(31)(32)(33)). We have taken the remarkable models described in (32) and (33) as our starting point, because of their direct applicability to the analysis of experimental data.…”

Section: Discussionmentioning

confidence: 99%

“…(30)(31)(32)(33)). We have taken the remarkable models described in (32) and (33) as our starting point, because of their direct applicability to the analysis of experimental data. The former provides a fully tractable quantitative description of the interplay between H + and HCO − 3 transporters with Na + /K + -ATPase and Na + , K + and Cl − ion fluxes, while the latter investigates the interaction of MCT transporters and CA9.…”

Section: Discussionmentioning

confidence: 99%

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The control of acidity in tumor cells: a biophysical model

Piasentin

Milotti²,

Chignola

2020

Preprint

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Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. The model takes into account the dynamic interplay between glucose and O 2 consumption with lactate and CO 2 production and connects these processes to H + and HCO − 3 fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. The simulations show a dominance of the H + exchanges in well-oxygenated regions, and of HCO − 3 exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. The model also includes the activity of the enzyme Carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear pH i equalizer at any O 2 level in cells that grow in acidic extracellular environments. SIGNIFICANCE The activity of cancer cells in solid tumors affects the surrounding environment in many ways, and an elevated acidity is a common feature of the tumor microenvironment. In this paper we propose a model of intracellular/extracellular acidity that is linked to cellular metabolism and includes all the main molecular players. The model is reliable, robust and validated with experimental data and can be used as an essential building block of more comprehensive in silico research on solid tumors. § current address:

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The control of acidity in tumor cells: a biophysical model

Piasentin

Milotti²,

Chignola

2020

Preprint

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“…In such an environment, efficient proton handling seems crucial for protoncoupled lactate transport across the membrane. We have previously suggested that intracellular and extracellular carbonic anhydrases can function as "proton antennae" for MCTs by mediating the rapid exchange of protons between the transporter pore and the surrounding protonatable residues [29, [64][65][66][67]. In CAIX, proton transfer between MCT and surrounding protonatable residues seems to be mediated by acidic residues within the enzyme's proteoglycan-like domain [30].…”

Section: Discussionmentioning

confidence: 99%

CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells

Ames

Andring

McKenna

et al. 2019

Preprint

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Tumor cells rely on glycolysis to meet their elevated demand for energy. Thereby they produce significant amounts of lactate and protons, which are exported via monocarboxylate transporters (MCTs), supporting the formation of an acidic microenvironment. The present study demonstrates that carbonic anhydrase IX (CAIX), one of the major acid/base regulators in cancer cells, forms a protein complex with MCT1 and MCT4 in tissue samples from human breast cancer patients, but not healthy breast tissue. Formation of this transport metabolon requires binding of CAIX to the Ig1 domain of the MCT1/4 chaperon CD147 and is required for CAIX-mediated facilitation of MCT1/4 activity. Application of an antibody, directed against the CD147-Ig1 domain, displaces CAIX from the transporter and suppresses CAIX-mediated facilitation of proton-coupled lactate transport. In cancer cells, this "metabolon disruption" results in a decrease in lactate transport, reduced glycolysis and ultimately reduced cell proliferation. Taken together, the study shows that carbonic anhydrases form transport metabolons with acid/base transporters in human tumor tissue and that these interactions can be exploited to interfere with tumor metabolism and proliferation.

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“…Both CAIV and CAIX have been suggested to function as an extracellular H + antenna for MCTs, which shuttles H + between the transporter and surrounding protonatable residues, thereby counteracting the formation of extracellular H + nanodomains ( Figure 2) [91,94,96]. Since dissipation of the proton nanodomain on only one side of the membrane could exacerbate the accumulation or depletion of protons on the other side, due to increased MCT transport activity, and intracellular and extracellular CAs have to work in concert for efficient proton handling on both sides of the membrane to allow maximum MCT transport activity ( Figure 2) [90,93].…”

Section: Transporter Interacts With Ca Isoformmentioning

confidence: 99%

“…Experiments on Xenopus oocytes and mathematical modeling have shown that efficient lactate shuttling via MCTs requires a carbonic anhydrase on both sides of the plasma membrane [90,93]. Even though the intracellular isoform CAII is not cancer specific, it is upregulated in different tumor cells, including breast, lung, colorectal, gastrointestinal, and prostate cancer [126][127][128][129].…”

Section: The Role Of Transport Metabolons In Tumor Metabolismmentioning

confidence: 99%

Transport Metabolons and Acid/Base Balance in Tumor Cells

Becker

Deitmer

2020

Cancers

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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.

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Modeling of pH regulation in tumor cells: Direct interaction between proton-coupled lactate transporters and cancer-associated carbonicanhydrase

Cited by 9 publications

References 37 publications

The control of acidity in tumor cells: a biophysical model

The control of acidity in tumor cells: a biophysical model

CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells

Transport Metabolons and Acid/Base Balance in Tumor Cells

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