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.

Figure 1. Monocarboxylate transporter 1 and 4 (MCT1 and MCT4) regulation

Blue boxes indicate upregulation of the specific MCT subtype while green boxes indicate a downregulation. There is no distinction between transcriptional versus translational regulation. HIF: Hypoxia-inducible transcription factor; MCT: Monocarboxylate transporter; NO: Nitric oxide.

Figure 2. CD147 signaling and interactions

Black arrows indicate stimulation/activation. Gray arrows indicate associated molecules and their additional signaling or augmentation of effect. MCT: Monocarboxylate transporter; MMP: Matrix metalloproteinase.

Figure 3. Potential metabolic pathways between tumor cells (see left)

Cells close to vessels will have the advantage of high/adequate concentrations of oxygen and nutrients, such as glucose. Cells farther from vessels will experience varying degrees of hypoxia and starvation. (A) The metabolic pathways possible between cancer cells without MCT1 inhibition when the aerobic cells are able to consume/utilize lactate. Shown here is the Pasteur effect (anaerobic glycolysis) in the hypoxic cells farther from vessels. The well-oxygenated cells close to vessels may undergo healthy oxidative phosphorylation, possibly the Warburg effect (aerobic glycolysis), or lactate utilization. (B) Illustrates the consequences of MCT1 inhibition on cell-to-cell metabolism and intracellular pH. MCT4, having a high K_m, is unlikely to take up lactate unless there is a very high extracellular concentration of lactate. Excluded from this diagram are pH regulators other than MCTs, such as Na⁺/H⁺ exchanger (NHE1), which would serve to remove some of the H⁺ from the cell. MCT1 inhibition can lead to cell death by two different means: the hypoxic cells are starved since cells close to vessels are forced to only take up glucose since the ability of lactate consumption is blocked, as seen by comparing (A) to (B) or the decrease in intracellular pH leads to toxicity, indicated by the protons represented in the diagram.

Figure 4. Influence of CD147 silencing on MCT expression, tumor cell lactate metabolism and MMP regulation in neighboring fibroblasts

Above tumor cell (left) has upregulated CD147 expression on the surface and adequate membrane expression of MCT subtypes 1 and 4, which allows various metabolic options for the cell (see Figure 3). Overexpression of CD147 can lead to increased matrix metalloproteinase production by neighboring fibroblasts (right). Bottom tumor cell shows the consequences of CD147 silencing with either CD147 siRNA or monocarboxylate transporter 4 (MCT4) siRNA. The gold bubble indicates the difference between these two. With MCT4 siRNA, CD147 is present in the cell, but in the low glycosylated form and therefore restricted to the cytosol. With CD147 siRNA, CD147 expression is ablated. Both scenarios lead to decreased MCT1 and MCT4 membrane expression, which will prevent monocarboxylate transport in and out of the cell. Lack of mature CD147 expression on the cell surface will also reduce MMP production by fibroblasts in comparison with a tumor cell with high CD147 expression. MCT: Monocarboxylate transporter; MMP: Matrix metalloproteinase.