Abstract
Here we investigated the impact of WNT5A signaling on aerobic glycolysis and evaluated its effects on breast cancer cell migration/invasion. WNT5A signaling reduced migration and lactate production and caused selective down-regulation of the glycolytic enzyme phosphofructokinase platelet-type (PFKP). These events occurred in parallel with a WNT5A-induced inhibition of β-catenin signaling. Support for essential involvement of β-catenin and PFKP in lactate production and migration/invasion was obtained by siRNA knockdown of their expression. To also explore the effect of non-tumor cell-derived lactate, we added exogenous lactate to the cells and noted an increase in migration that was significantly impaired by recombinant WNT5A in parallel with a down-regulation of the lactate transporter monocarboxylate transporter 1 (MCT1). Interestingly enough, the drug-candidate Foxy5 (WNT5A-mimic hexapeptide) also inhibited breast cancer cell migration in the presence of exogenous lactate, suggesting a therapeutic potential for Foxy5 in managing breast tumors with high glycolytic activity. Overall, we demonstrated that WNT5A signaling (via a β-catenin-PFKP axis) reduces lactate production and lowers the expression of MCT1, a carrier mediating the uptake of lactate from the tumor microenvironment. These effects of WNT5A are essential for its ability to impair breast cancer migration/invasion even in an environment with elevated lactate levels.
Highlights
Tumor growth depends on glucose uptake from the extracellular environment and its glycolytic breakdown resulting in accumulation of lactate even if O2 is present
To address this problem, we transfected two metastatic breast cancer cell lines (MDA-MB-468 and MDA-MB-231) with a WNT5A plasmid as these cells have no endogenous WNT5A expression (Supplementary Figure 1). Both breast cancer cell lines expressing the WNT5A plasmid (MDA-MB-468-5A and MDA-MB-231-5A) showed significant decreases in lactate production after 72 h compared to the respective empty vector (EV)-transfected control cells (Figure 1A and 1B). These findings clearly demonstrated that WNT5A signaling inhibits lactate production in breast cancer cells, which is in direct contrast to its effect in melanoma cells
The breast cancer cell lines used in the present study (MDA-MB-468 and MDA-MB-231) both lack endogenous expression of WNT5A protein, making them ideal to study the effects of WNT5A signaling via either transfection with a WNT5A plasmid or direct stimulation with recombinant WNT5A (rWNT5A) or Foxy5, a WNT5A-mimic peptide
Summary
Tumor growth depends on glucose uptake from the extracellular environment and its glycolytic breakdown resulting in accumulation of lactate even if O2 is present. This metabolic phenomenon is known as the ‘Warburg effect’ [1]. The increased aerobic glycolysis results in accumulation of lactate both inside and outside of the tumor cells, i.e., in the extracellular tumor microenvironment. Stromal cells in the tumor microenvironment can contribute to the accumulation of lactate and thereby exposing tumor cells to a high lactate concentrations [2,3,4,5]. The lactate concentration in tumors has been estimated to be as high as 40 mM compared to the physiologic normal range of 0.5–2 mM [6]
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