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Reduced production and uptake of lactate are essential for the ability of WNT5A signaling to inhibit breast cancer cell migration and invasion.

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 ?-catenin signaling. Support for essential involvement of ?-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 ?-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.

SUBMITTER: Prasad CP

PROVIDER: S-EPMC5641063 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Reduced production and uptake of lactate are essential for the ability of WNT5A signaling to inhibit breast cancer cell migration and invasion.

Prasad Chandra Prakash CP Södergren Katja K Andersson Tommy T

Oncotarget 20170420 42

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 obt ...[more]

PMID: 29069720

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Reduced production and uptake of lactate are essential for the ability of WNT5A signaling to inhibit breast cancer cell migration and invasion.

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Reduced production and uptake of lactate are essential for the ability of WNT5A signaling to inhibit breast cancer cell migration and invasion.

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