SLC7A5 is required for cancer cell growth under arginine-limited conditions
Summary: 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 path...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014815 |
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| _version_ | 1841560115796246528 |
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| author | Kyle N. Dunlap Austin Bender Alexis Bowles Alex J. Bott Joshua Tay Allie H. Grossmann Jared Rutter Gregory S. Ducker |
| author_facet | Kyle N. Dunlap Austin Bender Alexis Bowles Alex J. Bott Joshua Tay Allie H. Grossmann Jared Rutter Gregory S. Ducker |
| author_sort | Kyle N. Dunlap |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-7165d4fdab9f4daa90153ba6a0571ec7 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-7165d4fdab9f4daa90153ba6a0571ec72025-01-05T04:27:55ZengElsevierCell Reports2211-12472025-01-01441115130SLC7A5 is required for cancer cell growth under arginine-limited conditionsKyle N. Dunlap0Austin Bender1Alexis Bowles2Alex J. Bott3Joshua Tay4Allie H. Grossmann5Jared Rutter6Gregory S. Ducker7Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USADepartment of Pathology, University of Utah, Salt Lake City, UT 84112, USADepartment of Pathology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724014815CP: CancerCP: Metabolism |
| spellingShingle | Kyle N. Dunlap Austin Bender Alexis Bowles Alex J. Bott Joshua Tay Allie H. Grossmann Jared Rutter Gregory S. Ducker SLC7A5 is required for cancer cell growth under arginine-limited conditions Cell Reports CP: Cancer CP: Metabolism |
| title | SLC7A5 is required for cancer cell growth under arginine-limited conditions |
| title_full | SLC7A5 is required for cancer cell growth under arginine-limited conditions |
| title_fullStr | SLC7A5 is required for cancer cell growth under arginine-limited conditions |
| title_full_unstemmed | SLC7A5 is required for cancer cell growth under arginine-limited conditions |
| title_short | SLC7A5 is required for cancer cell growth under arginine-limited conditions |
| title_sort | slc7a5 is required for cancer cell growth under arginine limited conditions |
| topic | CP: Cancer CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014815 |
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