Tumor Metabolism of Lactate: The Influence and Therapeutic Potential for MCT and CD147 Regulation

Abstract

Tumor metabolism consists of complex interactions between oxygenation states, metabolites, ions, the vascular network and signaling cascades. Accumulation of lactate within tumors has been correlated with poor clinical outcomes. While its production has negative implications, potentially contributing to tumor progression, the implications of the ability of tumors to utilize lactate can offer new therapeutic targets for the future. Monocarboxylate transporters (MCTs) of the SLC16A gene family influence substrate availability, the metabolic path of lactate and pH balance within the tumor. CD147, a chaperone to some MCT subtypes, contributes to tumor progression and metastasis. The implications and consequences of lactate utilization by tumors are currently unknown; therefore future research is needed on the intricacies of tumor metabolism. The possibility of metabolic modification of the tumor microenvironment via regulation or manipulation of MCT1 and CD147 may prove to be promising avenues of therapeutic options. KeywordsCancer; CD147; lactate; MCT1; MCT1 inhibitors; MCT4; tumor metabolism Much of the past research on lactate in cancer has focused on its production. Under the influence of hypoxia, glucose is catabolized to lactate via glycolysis to yield ATP; mitochondria cannot produce ATP in oxidative phosphorylation without oxygen to aid in electron transport. This type of production is termed the 'Pasteur effect.' Cancer cells can also produce lactate under aerobic conditions. The switch from a 'normal' metabolic profile, consisting of glycolysis followed by oxidative phosphorylation, to cytosolic glycolysis in the presence of adequate oxygen, is termed the 'Warburg effect.' The discovery of aerobic glycolysis resulting in increased lactate production within tumors in the 1920-1930s by Otto Warburg led to a reevaluation of the potential role and significance of lactate in cancer studies [1][2][3][4]. Since the pioneering work of Warburg, production and accumulation of lactate has been documented to have clinical significance in a number of different cancer types. In the 1970s, lactate metabolism in malignant metastatic carcinomas and colorectal cancers was beginning to be explored with blood samples from patients that were injected or infused with radio-labeled glucose and pyruvate [5,6]. These studies indicated that lactate levels in plasma and venous †Author NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript blood were elevated in patients with metastatic cancer [6]. Nuclear magnetic resonance (NMR) studies following the fate of 13 C-labeled lactate are still used today.In the 1980s, quantitative bioluminescence imaging was used to assess metabolites such as lactate and glucose from flash-frozen biopsies to study ischemia in brain tissue [7,8]. This technique was later applied to assess these same metabolites in cancer [9][10][11]. More recent studies investigating lactate accumulation in human tumors have found that cervical tumors, head and neck cancers and rectal adenoc...

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

“…Accordingly, forced overexpression of either of the partners (resulting in the stabilization of both of them as previously reported in other systems) [13][14][15] was sufficient to promote TC migration (Figure 6f and Supplementary Figure 6C). The contribution of MCT1 to migration was seen with glucose or serum as chemoattractants but not with lactate or glutamine used at their relevant concentrations in culture media (Supplementary Figure 6B), explaining why others in non-metabolically controlled systems failed to detect MCT1-dependent migration other than random.…”

“…11,12,14 This basic information, however, is essential for the prediction of treatment sensitivity and resistance as well as for the rational design of combination therapies. In this study, we report that mitochondria deprived from glycolytic fuels stabilize the expression of MCT1 and of its chaperone protein CD147/basigin in human TCs, thus providing a functional complex known to be involved in the transport of monocarboxylic acids (through MCT1) and in the activation of matrix metalloproteinases (through CD147).…”

“…In this study, we report that mitochondria deprived from glycolytic fuels stabilize the expression of MCT1 and of its chaperone protein CD147/basigin in human TCs, thus providing a functional complex known to be involved in the transport of monocarboxylic acids (through MCT1) and in the activation of matrix metalloproteinases (through CD147). 11,14,15 Upon glucose starvation, the complex promoted TC migration towards serum and glucose. Our study identifies a functional link between impaired mitochondrial activity and TC migration wherein the mitochondrion acts as a glucose sensor and signals via ROS MCT1-dependent TC escape to a more favorable metabolic environment.…”

“…This paradigm offers a rationale for clinical data associating high MCT1 and CD147 expression to increased metastatic burden 10,14,32 and for the metastatic phenotype promoted by therapies limiting glucose availability in tumors. 31 We propose MCT1 inhibition as a pharmacological option to counter these effects.…”

“…12 At the posttranslational level, the membrane expression and transport activities of MCT1 require its direct interaction with the scaffold protein CD147. [13][14][15] The assembly of the complex exerts a stabilizing effect, which is necessary for the trafficking, cell surface localization and function of both proteins. In this study, we focused on tumor parameters and report that glucose deprivation posttranslationally stabilizes both MCT1 and CD147.…”