Abstract
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.
Original language | English (US) |
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Article number | 114552 |
Journal | Cell reports |
Volume | 43 |
Issue number | 8 |
DOIs | |
State | Published - Aug 27 2024 |
Funding
We thank Dr. Jiyeon Kim and Dr. Isaac Harris for their helpful discussions and reagents. This work was supported by National Cancer Institute R37 CA251216 to J.L.C., R01 CA200669 to J.F., and U54-CA225088 to P.K.S.; and the Harvard Ludwig Center for Cancer Research and the Termeer Foundation (P.K.S.).
Keywords
- ASCT2
- CP: Cancer
- ERα
- SLC1A5
- amino acid uptake
- breast cancer
- cancer metabolism
- diet
- purine biosynthesis
- serine starvation
- serine transporter
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology