Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Najumudeen, AK; Ceteci, F; Fey, SK; Hamm, G; Steven, RT; Hall, H; Nikula, CJ; Dexter, A; Murta, T; Race, AM; Sumpton, D; Vlahov, N; Gay, DM; Knight, JRP; Jackstadt, R; Leach, JDG; Ridgway, RA; Johnson, ER; Nixon, C; Hedley, A; Gilroy, K; Clark, W; Malla, SB; Dunne, PD; Rodriguez-Blanco, G; Critchlow, SE; Mrowinska, A; Malviya, G; Solovyev, D; Brown, G; Lewis, DY; Mackay, GM; Strathdee, D; Tardito, S; Gottlieb, E; Takats, Z; Barry, ST; Goodwin, RJA; Bunch, J; Bushell, M; Campbell, AD; Sansom, OJ, , CRUK, Rosetta, Grand, Challenge, Consortium.
The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer.
Nat Genet. 2021; 53(1):16-26
Doi: 10.1038/s41588-020-00753-3
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- Co-Autor*innen der Med Uni Graz
- Rodriguez Blanco Giovanny
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- Abstract:
- Oncogenic KRAS mutations and inactivation of the APC tumor suppressor co-occur in colorectal cancer (CRC). Despite efforts to target mutant KRAS directly, most therapeutic approaches focus on downstream pathways, albeit with limited efficacy. Moreover, mutant KRAS alters the basal metabolism of cancer cells, increasing glutamine utilization to support proliferation. We show that concomitant mutation of Apc and Kras in the mouse intestinal epithelium profoundly rewires metabolism, increasing glutamine consumption. Furthermore, SLC7A5, a glutamine antiporter, is critical for colorectal tumorigenesis in models of both early- and late-stage metastatic disease. Mechanistically, SLC7A5 maintains intracellular amino acid levels following KRAS activation through transcriptional and metabolic reprogramming. This supports the increased demand for bulk protein synthesis that underpins the enhanced proliferation of KRAS-mutant cells. Moreover, targeting protein synthesis, via inhibition of the mTORC1 regulator, together with Slc7a5 deletion abrogates the growth of established Kras-mutant tumors. Together, these data suggest SLC7A5 as an attractive target for therapy-resistant KRAS-mutant CRC.
- Find related publications in this database (using NLM MeSH Indexing)
- 5' Untranslated Regions - genetics
- Amino Acid Transport System ASC - metabolism
- Animals - administration & dosage
- Carcinogenesis - pathology
- Cell Proliferation - administration & dosage
- Colorectal Neoplasms - genetics, pathology
- Gene Expression Regulation, Neoplastic - administration & dosage
- Glutamine - metabolism
- Humans - administration & dosage
- Intestinal Mucosa - metabolism, pathology
- Kaplan-Meier Estimate - administration & dosage
- Large Neutral Amino Acid-Transporter 1 - metabolism
- Mechanistic Target of Rapamycin Complex 1 - metabolism
- Mice, Inbred C57BL - administration & dosage
- Minor Histocompatibility Antigens - metabolism
- Mutation - genetics
- Neoplasm Metastasis - administration & dosage
- Oncogenes - administration & dosage
- Proto-Oncogene Proteins p21(ras) - genetics
- RNA, Messenger - genetics, metabolism
- Signal Transduction - administration & dosage
- TOR Serine-Threonine Kinases - metabolism