ASCT2 is a major contributor to serine uptake in cancer cells.

The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo , others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporters that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that estrogen receptor α (ERα) promotes serine uptake by directly activating SLC1A5 transcription. Collectively, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target. [Display omitted] • ASCT2 contributes to serine uptake in cancer cells • Serine and glutamine compete for uptake via ASCT2 • ERα promotes serine uptake by directly activating SLC1A5 transcription • Loss of ASCT2 combined with dietary serine starvation shrinks xenograft tumors Despite significant interest in targeting serine metabolism for cancer therapy, the transporters that mediate serine uptake in cancer cells are not known. Conger et al. describe the amino acid transporter ASCT2 as a major contributor to serine uptake in cancer cells that is required for tumor growth in low-serine conditions. [ABSTRACT FROM AUTHOR]