Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon

Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels b...

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Bibliographic Details
Published in:Pharmacology & therapeutics (Oxford) 2020-02, Vol.206, p.107451-107451, Article 107451
Main Authors: Brown, Timothy P., Ganapathy, Vadivel
Format: Article
Language:English
Subjects:
Acidic microenvironment
Angiogenesis
Animals
Cancer-Associated Fibroblasts - metabolism
Chemoresistance
Humans
Immune evasion
Lactate/GPR81
Lactic Acid - metabolism
Membrane Transport Proteins - metabolism
Neoplasms - metabolism
Neovascularization, Pathologic - metabolism
Nutrient supply
Proton-Motive Force
Receptors, G-Protein-Coupled - metabolism
Signal Transduction
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Summary:Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels but also creating an acidic pH in extracellular milieu. Lactate and protons in tumor microenvironment are not innocuous bystander metabolites but have special roles in promoting tumor-cell proliferation and growth. Lactate functions as a signaling molecule by serving as an agonist for the G-protein-coupled receptor GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, cancer cell-generated lactate activates GPR81 on cancer cells; in the paracrine pathway, cancer cell-generated lactate activates GPR81 on immune cells, endothelial cells, and adipocytes present in tumor stroma. The end result of GPR81 activation is promotion of angiogenesis, immune evasion, and chemoresistance. The acidic pH creates an inwardly directed proton gradient across the cancer-cell plasma membrane, which provides driving force for proton-coupled transporters in cancer cells to enhance supply of selective nutrients. There are several molecular targets in the pathways involved in the generation of lactic acid by cancer cells and its role in tumor promotion for potential development of novel anticancer therapeutics.
ISSN:0163-7258
1879-016X
DOI:10.1016/j.pharmthera.2019.107451