Identification of ASCT2 as the Primary Serine Transporter in Cancer

Amino acid metabolism is central to cancer cell’s ability to proliferate, evade the immune system, and resist cell death. To acquire amino acids cells can utilize several mechanisms: de novo synthesis of nonessential amino acids, autophagy, macropinocytosis, and uptake of exogenous free amino acids. Recently, the non-essential amino acid serine has gained significant interest for its role in protein, nucleotide, lipid, and antioxidant metabolism. As a key contributor to cancer cell growth, serine metabolism has already been targeted for cancer therapy. Serine synthesis inhibitors have been developed and tested, but fail to account for redundant sources of exogenous serine. Systemic serine depletion has also been investigated as a way to limit the supply of exogenous serine, but may have costly side-effects. Reducing serine uptake by directly inhibiting serine transporters is a targeted approach to depriving cancer cells of a vital nutrient. Unfortunately, serine transporters have not yet been identified. Here, we characterize the amino acid transporter ASCT2 (coded for by the gene SLC1A5) as the dominant serine transporter in cancer cells. ASCT2 has previously been recognized as an important glutamine transporter in cancer, as many tumors are considered “glutamine-addicted”. However, we present the first evidence that ASCT2 contributes directly to serine uptake in a range of cancer cell lines. We further show that glutamine and serine compete for uptake by ASCT2, and that serine-auxotrophic luminal breast cancer cells specifically upregulate ASCT2 in response to serine, not glutamine deprivation. Additionally, we find that ASCT2-mediated serine uptake directly effects purine nucleotide biosynthesis and define a novel mechanism of transporter regulation by ERα. Finally, we find that combining genetic ablation of ASCT2 with a serine-free diet led to tumor regression in a xenograft model of luminal breast cancer. The work presented here is the first to define a new role for ASCT2 as a serine transporter in cancer and evaluate ASCT2 as a potential therapeutic target in serine metabolism.