LAT1/SLC7A5-mediated amino acid uptake is regulated by redox signals triggered by formyl-peptide receptor 2

The rewiring of amino acid (AA) metabolism is a key characteristic of cancer metabolism. Cells can only synthesize nonessential AAs, but if the demands of highly proliferating cells don't meet the endogenous synthesis capacity, AAs must be acquired from outside. SLC7 belongs to the solute carrier transporters (SLC) superfamily and acts as a passive facilitative or secondary AA active transporter. LAT1/SLC7A5 acts as an antiporter that mediates the influx of several AAs into cells in exchange for the efflux of intracellular substrates. In tumor cells, LAT1/SLC7A5 overexpression is closely associated with proliferation, invasion, metastasis, and poor clinical prognosis. Formyl peptide receptor 2 (FPR2) belongs to the FPR family of GPCRs. Its activation regulates several biological processes and triggers NADPH oxidase assembly and, consequently, reactive oxygen species (ROS) generation. FPR2 stimulation also induces an increase in SLC1A5/ASCT2 and SLC7A11/xCT expression, which correlates with enhanced glutamine and cystine uptake, respectively. Herein, we analyze the LAT1/SLC7A5-mediated uptake of several essential AAs in FPR2-stimulated CaLu-6 and HCC1937 cells and prove: (i) the redox regulation of both LAT1/SLC7A5 and 4F2hc/SLC3A2/CD98, which form a heterodimer on the plasma membrane; (ii) the redox activation of the mTOR pathway and, in turn, of S6K1 and 4E-BP1, which stimulate protein synthesis; (iii) c-Myc and miR-126 regulation, which control LAT1/SLC7A5 synthesis at the transcriptional and post-transcriptional level, respectively. These findings provide new approaches for the development of novel therapeutic strategies for the treatment of human cancers.