Conger, K. O.; Chidley, C.; Ozgurses, M. E.; Zhao, H.; Kim, Y.; Semina, S. E.; Burns, P. A.; Rawat, V.; Sheldon, R.; Ben-Sahra, I.; Frasor, J.; Sorger, P. K.; DeNicola, G. M.; Coloff, J. L.

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 for serine and therefore reliant on the uptake of exogenous serine. Importantly, however, the transporter(s) that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5) as the primary serine transporter 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 ER promotes serine uptake by directly activating SLC1A5 transcription. Together, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target in serine metabolism.