ASCT2 is a major contributor to serine uptake in cancer cells
Kelly O. Conger,
Christopher Chidley,
Mete Emir Ozgurses,
Huiping Zhao,
Yumi Kim,
Svetlana E. Semina,
Philippa Burns,
Vipin Rawat,
Lina Lietuvninkas,
Ryan Sheldon,
Issam Ben-Sahra,
Jonna Frasor,
Peter K. Sorger,
Gina M. DeNicola,
Jonathan L. Coloff
Affiliations
Kelly O. Conger
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Christopher Chidley
Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
Mete Emir Ozgurses
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Huiping Zhao
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Yumi Kim
Department of Cancer Metabolism and Physiology, H. Lee. Moffitt Cancer Center, Tampa, FL, USA
Svetlana E. Semina
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Philippa Burns
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Vipin Rawat
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Lina Lietuvninkas
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Ryan Sheldon
Metabolic and Nutritional Programming, Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA
Issam Ben-Sahra
Robert H. Lurie Cancer Center, Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA
Jonna Frasor
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Peter K. Sorger
Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA
Gina M. DeNicola
Department of Cancer Metabolism and Physiology, H. Lee. Moffitt Cancer Center, Tampa, FL, USA
Jonathan L. Coloff
Department of Physiology and Biophysics, University of Illinois Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA; Corresponding author
Summary: 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.
