Abstract
High rate of glycolysis is a metabolic hallmark of cancer. While anaerobic glycolysis promotes energy production under hypoxia, aerobic glycolysis, the Warburg effect, offers a proliferative advantage through redirecting carbohydrate fluxes from energy production to biosynthetic pathways. To fulfill tumor cell needs, the glycolytic switch is associated with elevated glucose uptake and lactic acid release. Altered glucose metabolism is the basis of positron emission tomography using the glucose analogue tracer [18F]- fluorodeoxyglucose, a widely used clinical application for tumor diagnosis and monitoring. On the other hand, high levels of lactate have been associated with poor clinical outcome in several types of human cancers. Although lactic acid was initially considered merely as an indicator of the glycolytic flux, many evidences originally from the study of normal tissue physiology and more recently transposed to the tumor situation indicate that lactic acid, i.e. the lactate anion and protons, directly contributes to tumor growth and progression. Here, we briefly review the current knowledge pertaining to lactic acidosis and metastasis, lactate shuttles, the influence of lactate on redox homeostasis, lactate signaling and lactate-induced angiogenesis in the cancer context. The monocarboxylate transporters MCT1 and MCT4 have now been confirmed as prominent facilitators of lactate exchanges between cancer cells with different metabolic behaviors and between cancer and stromal cells. We therefore address the function and regulation of MCTs, highlighting MCT1 as a novel anticancer target. MCT1 inhibition allows to simultaneously disrupt metabolic cooperativity and angiogenesis in cancer with a same agent, opening a new path for novel anticancer therapies.
Keywords: Tumor metabolism, hypoxia, Warburg effect, lactate, lactic acidosis, monocarboxylate transporters, hypoxia-inducible factor-1, nuclear factor-B, glycolysis, anticancer therapies
Current Pharmaceutical Design
Title: Multiple Biological Activities of Lactic Acid in Cancer: Influences on Tumor Growth,Angiogenesis and Metastasis
Volume: 18 Issue: 10
Author(s): Suveera Dhup, Rajesh Kumar Dadhich, Paolo Ettore Porporato and Pierre Sonveaux
Affiliation:
Keywords: Tumor metabolism, hypoxia, Warburg effect, lactate, lactic acidosis, monocarboxylate transporters, hypoxia-inducible factor-1, nuclear factor-B, glycolysis, anticancer therapies
Abstract: High rate of glycolysis is a metabolic hallmark of cancer. While anaerobic glycolysis promotes energy production under hypoxia, aerobic glycolysis, the Warburg effect, offers a proliferative advantage through redirecting carbohydrate fluxes from energy production to biosynthetic pathways. To fulfill tumor cell needs, the glycolytic switch is associated with elevated glucose uptake and lactic acid release. Altered glucose metabolism is the basis of positron emission tomography using the glucose analogue tracer [18F]- fluorodeoxyglucose, a widely used clinical application for tumor diagnosis and monitoring. On the other hand, high levels of lactate have been associated with poor clinical outcome in several types of human cancers. Although lactic acid was initially considered merely as an indicator of the glycolytic flux, many evidences originally from the study of normal tissue physiology and more recently transposed to the tumor situation indicate that lactic acid, i.e. the lactate anion and protons, directly contributes to tumor growth and progression. Here, we briefly review the current knowledge pertaining to lactic acidosis and metastasis, lactate shuttles, the influence of lactate on redox homeostasis, lactate signaling and lactate-induced angiogenesis in the cancer context. The monocarboxylate transporters MCT1 and MCT4 have now been confirmed as prominent facilitators of lactate exchanges between cancer cells with different metabolic behaviors and between cancer and stromal cells. We therefore address the function and regulation of MCTs, highlighting MCT1 as a novel anticancer target. MCT1 inhibition allows to simultaneously disrupt metabolic cooperativity and angiogenesis in cancer with a same agent, opening a new path for novel anticancer therapies.
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Dhup Suveera, Kumar Dadhich Rajesh, Ettore Porporato Paolo and Sonveaux Pierre, Multiple Biological Activities of Lactic Acid in Cancer: Influences on Tumor Growth,Angiogenesis and Metastasis, Current Pharmaceutical Design 2012; 18 (10) . https://dx.doi.org/10.2174/138161212799504902
DOI https://dx.doi.org/10.2174/138161212799504902 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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