Lactate Shuttles in Breast Cancer Cells: a 'Super Athlete' Model

Abstract

Studies of lactate metabolism in vivo in humans and rodents have shown that lactate is not only an end product of glycolysis, but is an important fuel for active muscles and other tissues. The operation of lactate shuttles within and among cells, tissues and organs such as retina, brain, testis, liver, and cardiac and skeletal muscle under fully aerobic conditions is well established. Lactate is produced in significant amounts in cancer cells under fully aerobic conditions due to enhanced glycolysis, described as a "Warburg Effect," but the role of lactate and its transporters in cancer growth is poorly understood. PURPOSE: In this study, we sought to identify differences in the expression of monocarboxylate transporters (MCT) and lactate dehydrogenase isoforms (LDH) in two breast cancer cell lines (MCF-7 and MDA-MB-231) and a normal control untransformed primary breast cell line (184), to understand the role of lactate transporters in cancer growth. METHODS: Immunoblotting (IB) and Confocal laser scanning microscopy (CLSM) were used to examine the expression and the localization of LDH and MCT proteins in normal and cancer cell lines. Oxygen consumption and lactate production per hour were measured using a Clark-type oxygen electrode and spectrophotometry, respectively. RESULT: Our data show that MCT (1, 2, and 4), and LDH isoforms (A and B) are expressed in both normal and cancerous breast cells, except that MDA-MB-231 did not express MCT1. MCT1 was highly expressed in control 184l cells when compared to cancer cells. MCT4 was highly expressed in MDA-MB-231, and MCT2 was highly expressed in MCF-7. LDH was highly expressed in both cancerous cell lines compared to the normal cell line, and MCF-7 expressed mainly LDHB, while MDA-MB-231 and 184 expressed mainly LDHA. MCT2, MCT4, and LDH were localized in mitochondria in addition to the plasma membrane and cytosol, respectively, whereas MCT1 was localized in plasma membrane. This localization was the same in cancerous and normal cell lines. CONCLUSION: We report changes in the expression of MCT and LDH in breast cancer cells with no change in their localization. These changes corresponded to the breast cancer cells' oxidative capacity. Our data support the existence of the previously reported lactate shuttle in tumors. Lessons from exercise physiology may prove useful in terms of targeting and killing cancer cells. Conversely, metabolic adaptations to support the hypermetabolism of cancer cells may provide models for understanding metabolic adaptations to exercise training. Supported by NIH grant AR050459 and a gift from CytoSport, Inc.