SLC7A5 is required for cancer cell growth under arginine-limited conditions.
Publication Title
Cell Rep
Document Type
Article
Publication Date
1-28-2025
Keywords
oregon; chiles; Arginine; Animals; Humans; Mice; Cell Line, Tumor; Large Neutral Amino Acid-Transporter 1; Cell Proliferation; Neoplasms; Citrulline; Female
Abstract
Tumor cells must optimize metabolite acquisition between synthesis and uptake from a microenvironment characterized by hypoxia, lactate accumulation, and depletion of many amino acids, including arginine. We performed a metabolism-focused functional screen using CRISPR-Cas9 to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Using isotope tracing experiments, we show that citrulline uptake and metabolism into arginine are dependent upon expression of SLC7A5. Pharmacological inhibition of SLC7A5 blocks growth under low-arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. We identify a conditionally essential role for SLC7A5 in arginine metabolism, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be effective in the context of arginine limitation.
Area of Special Interest
Cancer
Specialty/Research Institute
Oncology
Specialty/Research Institute
Earle A. Chiles Research Institute
DOI
10.1016/j.celrep.2024.115130
