Massive conversion of glucose to lactic acid via glycolysis, for ATP production, is a feature of cells in a hypoxic tumor microenvironment. Consequently, tumor cells must efficiently export lactic acid to maintain a permissive intracellular pH and survive. Cells possess several transport systems for lactic acid extrusion. A large family of H+-linked MonoCarboxylate Transporters (MCTs) represented by the ubiquitously expressed MCT1, co-transport H+/lactate-. MCT4, a member of this family is widely expressed in tumor cells and up-regulated in hypoxia by the transcription factor HIF-1. In addition, the functional expression of MCT1 and MCT4 at the plasma membrane requires the specific interaction with the glycoprotein chaperone CD147/Basigin. Objectives of the study: Why do tumor cells express two (H+, Lactate-) co-transporters? What are their respective function? Are they both essential for tumor cell survival and growth? Methods: Exploit Ras-transformed fibroblasts defective either in respiration (GSK3) or glycolysis (DS7) and human tumor cell lines to assess the role of MCT1 and MCT4 in tumor growth. Evaluate the pharmacologic impact of the specific AstraZeneca MCT1 inhibitor on tumor growth in nude mice. Results: Firstly, most of the human tumor cell lines tested constitutively express MCT1 and induce MCT4 under hypoxic conditions. However, we found that Ras-transformed fibroblasts (wild type) and the melanoma cell line A375Tr, express only MCT1 under both normoxic and hypoxic conditions. In these cell lines blockade of the MCT1 lactate transporter with a MCT1 specific inhibitor (MCT1i, AstraZeneca) compromises maintenance of ATP production, and severely restricts cell growth in vitro under elevated glycolytic conditions (oligomycin treatment or hypoxia) and in vivo in xenografted tumors. Secondly, ectopic expression of human MCT4 in these fibroblasts and melanoma cells bypasses the MCT1 blockade. MCT4 expression, (i) restored in hypoxia, lactic acid extrusion, pHi control, ATP levels and growth and (ii) induced tumors to escape the MCT1 blockade in vivo. Respiration-deficient Ras-transformed fibroblasts (res-) that rely on a continuous supply of glucose for survival produce four times more lactic acid than parental fibroblasts. The tumor incidence and tumor growth rate of the res- mutant cells is highly reduced when compared to wild type fibroblasts. However, ectopic expression of MCT4 restored the full tumorigenicity of these \#8216;highly glycolytic\#8217; cells (res-) in nude mice. Conclusion: We have validated two key metabolic transporters: MCT4 and MCT1 as potentially valuable targets for anticancer therapy. In tumor cells that express only MCT1, the AstraZeneca inhibitor severely restricts tumor growth. Ablation of tumor growth of cells expressing both transporters would require combined inhibition, as shown by silencing of their common chaperone CD147/Basigin.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-44.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO