Dysregulated pH: a perfect storm for cancer progression

Webb, Bradley A.; Chimenti, Michael S.; Jacobson, Matthew P.; Barber, Diane L.

doi:10.1038/nrc3110

Cited by 1,907 publications

(1,753 citation statements)

References 110 publications

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“…This in turn may facilitate the activity of pro-migratory and pro-invasive enzymes and transporters, including matrix metalloproteinases. 46,47 On the other hand, the MCT1-CD147 complex is known to behave as a scaffold for other proteins involved in cell migration and invasion. 48 The composition of these supercomplexes is cell type-dependent and could logically be influenced by the cell environment and MCT1 expression and activity (conformation change).…”

Section: Discussionmentioning

confidence: 99%

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

et al. 2013

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The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins. In this study, we found that glucose deprivation dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this posttranslational induction could be recapitulated using glycolysis inhibition, hypoxia, oxidative phosphorylation (OXPHOS) inhibitor rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes accumulated, including in cell protrusions of the plasma membrane. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration increased in cells overexpressing MCT1 and CD147, but it was inhibited in glucose-starved cells provided with an alternative oxidative fuel, treated with an antioxidant, lacking MCT1 expression, or submitted to pharmacological MCT1 inhibition. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer.

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Section: Discussionmentioning

confidence: 99%

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

et al. 2013

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“…It is known that pH value of extracellular environment in several tumor histotype ranges from 6.7 to 7.1 [20]. Interestingly, extracellular acidosis maintains a high level of CAIX expression in tumor cells, in a HIF-1α-independent way [21].…”

Section: Why Tumor Microenvironment Is Often Characterized By Low Phmentioning

confidence: 99%

The acidic microenvironment as a possible niche of dormant tumor cells

Peppicelli

Andreucci

Ruzzolini

et al. 2017

Cell. Mol. Life Sci.

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“…This adaptive reversed pH gradient is decisive for survival and propagation of tumours, promotes metabolic adaptation, evasion of apoptosis and facilitates the metastatic dissemination of tumour cells. Consequently, pH is recently being considered as another hallmark of cancer [4].…”

Section: Introductionmentioning

confidence: 99%

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

Rodilla

Korrodi‐Gregório

Hernando

et al. 2017

Biochemical Pharmacology

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Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with different mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favors cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing body of evidence supporting ionophores as a novel antitumor drugs. Despite this, little is known about the implications of pH deregulation and homeostasis imbalance triggered by ionophores at the cellular level. In this work, we deeply analyze for the first time the anticancer effects of tambjamine analogues, a group of highly effective anion selective ionophores, at the cellular and molecular level. First, their effects on cell viability were determined in several lung cancer cell lines and patient-derived cancer stem cells, demonstrating their potent cytotoxic effects. Then, we have characterized the induced lysosomal deacidification, as well as, the massive cytoplasmic vacuolization observed after treatment with these compounds, which is consistent with mitochondrial swelling. Finally, the activation of several proteins involved in stress response, autophagy and apoptosis was also detected, although necrosis was the main mechanism of cell death induced.Altogether, these evidences suggest that tambjamine analogues provoke an imbalance in cellular ion homeostasis that triggers mitochondrial dysfunction and lysosomal deacidification leading to a potent cytotoxic effect through necrosis in lung cancer cell lines and cancer stem cells.

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Dysregulated pH: a perfect storm for cancer progression

Cited by 1,907 publications

References 110 publications

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

The acidic microenvironment as a possible niche of dormant tumor cells

Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

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