Tumor metabolism, cancer cell transporters, and microenvironmental resistance

Alfarouk, Khalid O.

doi:10.3109/14756366.2016.1140753

Cited by 66 publications

(50 citation statements)

References 150 publications

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“…The lower pH may mask the efficacy of chemotherapy by altering drug distribution and metabolism. This lower pH may also skew T and NK cells toward the immunosuppressive phenotype and function . The cytotoxicity of NK cells is detected to be impaired by 50% when providing an acidic microenvironment in which the pH values vary from 7.2 to 7.0.…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Long

Gao

et al. 2018

Cancer Medicine

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Monocarboxylate transporter‐4 (MCT4), a monocarboxylic acid transporter, demonstrates significantly increased expression in the majority of malignancies. We performed an experiment using BALB/C mice, and our results showed that ShMCT4 transfection or the pharmaceutic inhibition of MCT4 with 7acc1 strengthens the activity of NK cells. The results of a calcein assay revealed that the cytotoxicity of NK cells was strengthened via inhibition of MCT4. In addition, ELISA testing showed that the content of perforin and CD107a was increased, and PCR amplification and immunoblotting revealed that the expression of NKG2D and H60 was upregulated after the inhibition of MCT4. Further, we observed an elevated pH value, decreased extracellular lactate flow, and attenuated tumor growth. Therefore, we concluded that the inhibition of MCT4 enhanced the cytotoxicity of NK cells by blocking lactate flux and reversing the acidified tumor microenvironment. In addition to these findings, we also discovered that MCT4 depletion may have a pronounced impact on autophagy, which was surmised by observing that the inhibition of autophagy (3MA) pulled the enhanced cytotoxicity of NK cells downwards. Together, these data suggest that the key effect of MCT4 depletion on NK cells probably utilizes inductive autophagy as a compensatory metabolic mechanism to minimize the acidic extracellular microenvironment associated with lactate export in tumors.

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Section: Introductionmentioning

confidence: 99%

“…This lower pH may also skew T and NK cells toward the immunosuppressive phenotype and function. [10][11][12][13] The cytotoxicity of NK cells is detected to be impaired by 50% when providing an acidic microenvironment in which the pH values vary from 7.2 to 7.0. NK cell cytotoxicity may even drop to 0% if the pH value decreases to 6.5.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Long

Gao

et al. 2018

Cancer Medicine

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“…The metabolic change from oxidative phosphorylation to glycolysis in cancer cells has been reported in several studies, 27,28 and this metabolic change offered novel strategies for cancer treatment. Notably, we and others found that stimulation by RANKL during osteoclastogenesis induced a metabolic shift towards elevated glycolytic metabolism.…”

Section: Discussionmentioning

confidence: 91%

Inhibition of PFKFB3 suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

Wang

Guan

Liu

et al. 2019

J Cellular Molecular Medi

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Osteoclasts are multinucleated cells derived from the monocyte/macrophage cell lineage under the regulation of receptor activator of nuclear factor-κB ligand (RANKL).In previous studies, stimulation by RANKL during osteoclastogenesis was shown to induce a metabolic switch to enhanced glycolytic metabolism. Thus, we hypothesized that blockage of glycolysis might serve as a novel strategy to treat osteoclast-related diseases. In the present study, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), an essential regulator of glycolysis, was up-regulated during osteoclast differentiation. Genetic and pharmacological inhibition of PFKFB3 in bone marrow-derived macrophages suppressed the differentiation and function of osteoclasts. Moreover, intraperitoneal administration of the PFKFB3 inhibitor PFK15 prevented ovariectomy-induced bone loss. In addition, glycolytic activity characterized by lactate accumulation and glucose consumption in growth medium was reduced by PFKFB3 inhibition. Further investigation indicated that the administration of L-lactate partially reversed the repression of osteoclastogenesis caused by PFKFB3 inhibition and abrogated the inhibitory effect of PFK15 on the activation of NF-κB and MAPK pathways. In conclusion, the results of this study suggest that blockage of glycolysis by targeting PFKFB3 represents a potential therapeutic strategy for osteoclast-related disorders. K E Y W O R D Sglycolysis, MAPKs, NF-κB, osteoclast, PFKFB3

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“…Under aerobic conditions, O 2 binds a proton to form H 2 O; therefore, O 2 acts as an intracellular detoxifying molecule [1]. During transient low oxygen conditions and in only some relatively adaptable tissues (e.g., skeletal muscle but not in the brain nor heart) glycolysis produces lactate (converted from pyruvate), which is then translocated (extruded), via proton-linked monocarboxylate transporters (MCTs), creating an acidic extracellular pHe [2][3][4][5][6][7]. This transient shift in the metabolic program under oxygen scarcity is termed the "Pasteur effect" [8].…”

Section: Introductionmentioning

confidence: 99%

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

Alfarouk¹,

Ahmed

et al. 2020

Cancers

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Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism.

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Tumor metabolism, cancer cell transporters, and microenvironmental resistance

Cited by 66 publications

References 150 publications

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

Inhibition of PFKFB3 suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer

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