CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors.

Abstract

Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H(+)/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res(-)) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res(-) cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, highlighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H(+) symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin(high) cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy.

• Authors: Renaud Le Floch, Johanna Chiche, Ibtissam Marchiq, Tanesha Naiken, Tanesha Naïken, Karine Ilc, Karine Ilk, Clare M Murray, Susan E Critchlow, Danièle Roux, Marie-Pierre Simon, Jacques Pouysségur
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 40 Pg. 16663-8 (Oct 04 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21930917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR C155858
• DNA Primers
• Monocarboxylic Acid Transporters
• Muscle Proteins
• Protein Subunits
• SLC16A4 protein, human
• Symporters
• Thiophenes
• monocarboxylate transport protein 1
• Basigin
• Lactic Acid
• Uracil

Topics

• Basigin (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects, genetics)
• DNA Primers (genetics)
• Flow Cytometry
• Fluorescent Antibody Technique
• Gene Knockout Techniques
• Gene Silencing
• Glycolysis (drug effects)
• Humans
• Immunohistochemistry
• Lactic Acid (metabolism)
• Monocarboxylic Acid Transporters (antagonists & inhibitors, genetics, metabolism)
• Muscle Proteins (genetics, metabolism)
• Oxygen Consumption (physiology)
• Protein Subunits (genetics, metabolism)
• Symporters (antagonists & inhibitors, genetics, metabolism)
• Thiophenes (pharmacology)
• Uracil (analogs & derivatives, pharmacology)