Abstract 3225: Growth inhibition of glycolytic tumors by targeting basigin/lactate-H+ symporters (MCTs): Metformin sensitizes MCT inhibition
Authors: Floch Renaud Le , Chiche Johanna , Marchiq Ibtissam , Naiken Tanesha , Ilc Karine , Simon Marie-Pierre , Roux Danièle , Pouyssegur Jacques 
Published: August 2012

Intense conversion of glucose to lactic acid via glycolysis is a feature of rapidly growing cells often encountered in hypoxic tumor microenvironments. To survive and expand, tumor cells must efficiently export lactic acid to maintain intracellular pH. Cells possess several systems for lactic acid extrusion. A family of H+-linked MonoCarboxylate Transporters (MCTs) is represented by the ubiquitously expressed MCT1, a H+/lactate symporter that operates in both directions. MCT4, a close relative of MCT1, is up-regulated by HIF-1 and is highly expressed in aggressive malignant tumors. In addition, the functional expression of MCT1/MCT4 requires the interaction with the glycoprotein CD147/Basigin also known as EMMPRIN, a protumoral protein involved in invasion. Objectives: 1) Demonstrate that tumor growth is dependent on lactic acid export and that both transporters MCT1/MCT4 represent key anticancer targets. 2) Demonstrate whether the protumoral function of Basigin/CD147 is primary linked to lactic acid export or to other invasive functions. 3) Demonstrate whether Metformin, an inhibitor of mitochondrial complex I, sensitizes glycolytic tumor cells to MCTs inhibitors. Methods: We exploited two tumoral models. i) Ras transformed fibroblasts expressing only MCT1/MCT2 and ii) the human colon adenocarcinoma cell line LS174T expressing MCT1 and MCT4. We inhibited MCT1/MCT2 with the specific astraZeneca compound AR-C155858 and knocked-down MCT1, MCT4 and CD147 with inducible shRNAs. In addition we knocked-out mct4 or basigin with Zinc Finger Nucleases in LS174T cells. Results: First we demonstrated that silencing or pharmacological blockage of MCTs, reduced pHi, the rate of glycolysis and tumor growth in mice xenografts. This tumor growth inhibition was recapitulated by a single silencing or knock out of basigin/CD147 gene that also reduced the plasma membrane expression of MCT1 and MCT4 and lactate transport up to 10-fold. Second, to gain insight into CD147/Basigin function, we uncoupled MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin-high expressors, suppressed tumor growth. Conversely in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Thirdly, we showed that tumor cells lacking Basigin or MCT4 become highly sensitive to MCT1 inhibition when treated with Metformin. This synthetic lethality demonstrated in vitro and currently being tested in vivo will be discussed. Conclusions: These findings highlight that a 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 approach. Furthermore, we reveal that Metformin, by sensitizing normoxic cells to inhibitors of lactic export (MCTs), could offer an interesting novel anticancer strategy for rapidly growing tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3225. doi:1538-7445.AM2012-3225