Amino acid transporter LAT1 (SLC7A5) promotes metabolic rewiring in TNBC progression through the L-Trp/QPRT/NAD

backgroundCancer cells uptake excessive nutrients by expressing higher levels of glucose and/or amino acid transporters to meet their increased energy demands. L-type amino acid transporter 1 (LAT1), is regarded as a cancer-specific transporter for the uptake of large neutral amino acids such as L-tryptophan. However, the mechanism by which LAT1 rewires cellular metabolism to promote cancer progression and chemoresistance have not yet been investigated.

methodsThe protein levels of LAT1, p-PKM2, and p-LDHA were determined in breast cancer tissue arrays by immunohistochemistry staining followed by survival analysis. The orthotopic breast cancer models in mice, syngeneic breast cancer models, and patient-derived xenograft (PDX) mouse models were used to study the effects of LAT1 inhibition in tumor growth and chemoresistance. Steady-state polar metabolite analysis was performed to profile changes in cellular metabolism by LC-MS. The pyruvate and lactate assays as well as the seahorse assay using LAT1 knockdown cells and control cells were conducted to evaluate cellular glycolytic activities.

resultsThe LAT1 protein levels were positively correlated with poor survival in triple-negative breast cancer (TNBC) patients. LAT1 silencing resulted in reduced TNBC cell viability, proliferation, migration, invasion in vitro, as well as tumor growth in vivo. The knockdown of LAT1 reduced glycolytic activities via activating PKM2 and LDHA, two key glycolytic enzymes essential for cancer cell growth. Mechanistically, we demonstrated that LAT1 promoted de novo NAD + synthesis by facilitating L-tryptophan uptake and upregulating quinolinate phosphoribosyltransferase (QPRT), the rate-limiting enzyme in this pathway. This resulted in an increased cytosolic NAD

conclusionThese findings identify a novel role of LAT1 in promoting TNBC progression and chemo-resistance by amplifying the Warburg effect, positioning LAT1 as a promising therapeutic target for TNBC treatment.