Oncotarget

Research Papers:

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

Chandra Prakash Prasad _, Katja Södergren & Tommy Andersson

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Oncotarget. 2017; 8:71471-71488. https://doi.org/10.18632/oncotarget.17277

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Abstract

Chandra Prakash Prasad1, Katja Södergren1 and Tommy Andersson1

1Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Clinical Research Centre, Skåne University Hospital, SE-20502 Malmö, Sweden

Correspondence to:

Chandra Prakash Prasad, email: chandra.prasad@med.lu.se

Keywords: WNT5A, breast cancer cells, PFKP, lactate, cell migration and invasion

Received: February 02, 2017     Accepted: April 11, 2017     Published: April 20, 2017

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.


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