Clinical Role of ASCT2 (SLC1A5) in KRAS-Mutated Colorectal Cancer
Open accessAbstract
Mutation in the KRAS gene induces prominent metabolic changes. We have recently reported that KRAS mutations in colorectal cancer (CRC) cause alterations in amino acid metabolism. However, it remains to be investigated which amino acid transporter can be regulated by mutated KRAS in CRC. Here, we performed a screening of amino acid transporters using quantitative reverse-transcription polymerase chain reaction (RT-PCR) and then identified that ASCT2 (SLC1A5) was up-regulated through KRAS signaling. Next, immunohistochemical analysis of 93 primary CRC specimens revealed that there was a significant correlation between KRAS mutational status and ASCT2 expression. In addition, the expression level of ASCT2 was significantly associated with tumor depth and vascular invasion in KRAS-mutant CRC. Notably, significant growth suppression and elevated apoptosis were observed in KRAS-mutant CRC cells upon SLC1A5-knockdown. ASCT2 is generally known to be a glutamine transporter. Interestingly, SLC1A5-knockdown exhibited a more suppressive effect on cell growth than glutamine depletion. Furthermore, SLC1A5-knockdown also resulted in the suppression of cell migration. These results indicated that ASCT2 (SLC1A5) could be a novel therapeutic target against KRAS-mutant CRC.
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Many tumors driven by oncogenic KRAS and MYC reprogram metabolism to consume and rely more on glutamine for catabolic and anabolic pathways.
“Many tumors driven by oncogenic KRAS and its downstream effector, the transcription factor MYC, exhibit metabolic reprogramming to consume and rely more on glutamine for both catabolic to anabolic pathways55,56.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [55]
Glutamine uptake is enhanced in K-Ras-driven cells via upregulation of SLC1A5.
“Similar to the situation in MYC-driven cancer cells, glutamine uptake is enhanced in K-Ras-driven cells via upregulation of SLC1A5181.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [181]
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“Previous research has demonstrated that SLC1A5 can promote the survival, growth, and migration of colorectal cancer cells [15,26,27].”
Glutamine: a new strategy for targeted metabolic therapy in the tumor microenvironment
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“Moreover, mutant KRAS CRC cells were more dependent on the glutaminolysis pathway for energy supply than were wt KRAS CRC cells [52].”
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Tumor Metabolism: A New Field for the Treatment of Glioma
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“Alanine, serine, and cysteine transporter 2 (ASCT2), also known as SLC1A5, is an amino acid transporter that is upregulated in many cancers, including KRAS-mutant CRC (57).”
BackgroundWang, G., Wang, J., Yin, P., Xu, K., Wang, Y., Shi, F., Gao, J., & Fu, X. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27388 · Cited by 9 · see citing works
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“101”
Zhexian, L., Xingqi, G., Xinxin, D., Tong, X., Ma, S., & Yanxi, L. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1630279 · Cited by 6 · see citing works
“Given the therapeutic resistance commonly observed in KRAS-mutant tumors, ASCT2 represents a promising target for this CRC subset (144, 145).”
Hon, K. W., & Naidu, R. (2025) · Biomolecules · doi:10.3390/biom15101376 · Cited by 6 · see citing works
“Meanwhile, the upregulation of SLC1A5 in CRC tissues was significantly associated with enhanced tumour growth and survival [212,213].”
InfluentialAmino Acid Metabolism in Bone Metastatic Disease
Edwards, D. N. (2023) · Current Osteoporosis Reports · doi:10.1007/s11914-023-00797-4 · Cited by 6 · see citing works
Progesterone inhibits endometrial cancer growth by inhibiting glutamine metabolism through ASCT2
Guo, J., Fan, J., Zhang, Y., Li, M., Jin, Z., Shang, Y., Zhang, H., & Kong, Y. (2024) · Bioscience Reports · doi:10.1042/bsr20232035 · Cited by 6 · see citing works
“Furthermore, ASCT2 is up-regulated in various cancers, including tongue [19], lung [20,21], breast [18], pancreatic [22], gastric [23,24], colorectal [25], prostate [26], and renal cell cancer [27,28].”
BackgroundRas Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance
Río-Vilariño, A., del Puerto‐Nevado, L., García‐Foncillas, J., & Cebrián, A. (2021) · Cancers · doi:10.3390/cancers13153757 · Cited by 6 · see citing works
“There are some publications about the important role of GLUD1 (glutamine dehydrogenase 1) and SLC25A13 (Solute Carrier 25A13, an aspartate-glutamate mitochondrial carrier) for KRAS mutant CRC survival under glucose-deprivation conditions [156].”
BackgroundDuan, Z., Zhou, Z., Lu, F., Zhang, Y., Guo, X., Gui, C., & Zhang, H. (2022) · Investigational New Drugs · doi:10.1007/s10637-022-01284-w · Cited by 6 · see citing works
“Overexpression of SCL1A5 has been observed in primary CRC specimen in correlation to KRAS mutational status [10].”
BackgroundStructural basis of the obligatory exchange mode of human neutral amino acid transporter ASCT2
Borowska, A. M., Chiariello, M. G., Garaeva, A. A., Rheinberger, J., Marrink, . J., Paulino, C., & Slotboom, D. J. (2024) · Nature Communications · doi:10.1038/s41467-024-50888-8 · Cited by 6 · see citing works
“ASCT2 belongs to the solute carrier 1A (SLC1A) family of membrane transporters, which in humans also includes the related exchanger ASCT1 and fi ve subtypes of excitatory amino acid transporters (EAAT1 – 5) 7 .”
Wu, D., Zhu, C.-B., Pan, H., Xu, H., Xu, J., Liu, Y., Wang, S., Xiao, M.-M., Yu, X.-J., & Shi, S. (2026) · Gut · doi:10.1136/gutjnl-2025-336235 · Cited by 5 · see citing works
Almeida, C., Teixeira, A. L., Dias, F., Machado, V., Morais, M., Martins, G., Palmeira, C., Sousa, M. E., Godinho, I., Batista, S., et al. (2022) · Biology · doi:10.3390/biology11010145 · Cited by 5 · see citing works
“Interestingly, Toda and co-workers observed that ASCT2-knockdown presents a more suppressive effect on cell growth than glutamine depletion [27].”
BackgroundRAS: Circuitry and therapeutic targeting
Singh, G., Thakur, N., & Kumar, U. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110505 · Cited by 5 · see citing works
Mao, Z., Luo, S., Zhao, D., Zhou, X., Zhang, Z.-L., Xiao, Y., Cao, S., Zhou, Y., Liu, S.-J., Tang, J.-Z., et al. (2021) · Fishes · doi:10.3390/fishes6040077 · Cited by 4 · see citing works
“Although ASCT2 was named by the acronym of Alanine, Serine, Cysteine Transporter 2, the preferred substrate of ASCT2 is glutamine [9,10].”
BackgroundThe Regulation and Function of the Amino Acid Transporters LAT1, ASCT2, xCT in Urological Cancers
Zhao, X., Sakamoto, S., Saito, S., Pae, S., Yamada, Y., Kanaoka, S., Wei, J., Goto, Y., Sazuka, T., Imamura, Y., et al. (2024) · Receptors · doi:10.3390/receptors3040024 · Cited by 4 · see citing works
“…expression correlates with poorer overall and recurrence-free survival in gastric cancer [45], hepatocellular carcinoma [46], colorectal cancer [47], non-small cell lung cancer [48,49], clear cell renal cell carcinoma [50], ovarian cancer [51], breast cancer [52], and adrenal pheochromocytomas…”
GLUT1 and ASCT2 expression and their prognostic value in colorectal carcinoma
Ibrahiem, A. T., Refat, S., Elnaghi, K., Emarah, Z. A., & Nagib, R. M. (2023) · Indian Journal of Pathology and Microbiology · doi:10.4103/ijpm.ijpm_78_23 · Cited by 4 · see citing works
Therapeutic Targeting of Glutamine Metabolism in Colorectal Cancer
Ratre, Y. K., Verma, H. K., Mehta, A., Soni, V. K., Sonkar, S. C., Shukla, D., Ekka, A., Prajapati, S. K., Mahilkar, S., & Vishvakarma, N. K. (2021) · Springer eBooks · doi:10.1007/978-3-030-64668-4_15 · Cited by 4 · see citing works
Identification of potential core genes in hepatoblastoma via bioinformatics analysisPreprint
Vastrad, B. M., Vastrad, C. M., & Kotturshetti, I. (2020) · medRxiv · doi:10.1101/2020.12.22.20248756 · Cited by 3 · see citing works
“0) M917 Complement Pathway 2.38E-12 3.19E-10 1.75E-09 3.19E-10 11 MBL2,MASP2,MASP1,CF B,C1R,C1S,C5,C6,C7,C8A ,C9 M15997 Intrinsic Prothrombin Activation Pathway 3.88E-07 1.30E-05 7.12E-05 5.20E-05 8 F8,F9,F11,FGB,FGG,SER PINC1,KLKB1,KNG1 M5885 Ensemble of genes encoding ECM-associated proteins including ECM-affilaited…”
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“Intra-tumoral erythrocytes served as a positive control, and negative control staining was performed without applying the primary antibody.(39,40)”
MethodGlutamine transporters as effective targets in digestive system malignant tumor treatment
CHU, F., TONG, K., Gu, X., BAO, M., Chen, Y., Wang, B., SHAO, Y., & Wei, L. (2024) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.32604/or.2024.048287 · Cited by 2 · see citing works
“High ASCT2 expression is considerably associated with KRAS mutations in CRC, and ASCT2 knockdown inhibits CRC cell growth [23].”
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Lv, B., Xu, R., Xing, X., Liao, C., Zhang, Z., Zhang, P., & Xu, F. (2022) · Metabolites · doi:10.3390/metabo12060494 · Cited by 1 · see citing works
“For example, it has been reported that SCL1A5 (Solute Carrier family 1, Member 5), a glutamine transporter, was upregulated in CRC [23,24].”
BackgroundDetection of Adenocarcinoma of the Colon on 18F-Fluciclovine PET/CT
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LINC01134 Directly Binds and Regulates SLC1A5 Stability to Promotes Colorectal Cancer Progression
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“Furthermore, SLC1A5 knockdown inhibited CRC cell proliferation and migration and increased the efficacy of cetuximab on CRC[12, 26].”
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“Interestingly, the expression of pyruvate dehydrogenase kinases 4 (PDHK4) increases the synthesis rate of high fatty acids, indicating the critical role of lipid metabolism,68 and the failure of PDHK4 may affect the relationship between KRAS and the plasma membrane.23 KRAS is modified by CAAX prenylation allowing it t…”
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“A previous study suggested that ASCT2 can be a prognostic marker in KRAS-mutant CRC clinical specimens, and its overexpression is positively related with cancer invasion and migration [18].”
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- Authors
- Toda, K., Nishikawa, G., Iwamoto, M., Itatani, Y., Takahashi, R., Sakai, Y., & Kawada, K.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Kawada, Kenji
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2017-07-27
- Volume
- 18
- Issue
- 8
- Pages
- 1632
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC5578022
- OpenAlex
- W2737869011
- Cited by
- 77
- References
- 37
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 17 · 2023: 8 · 2022: 8 · 2021: 12 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 1
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- ASCT2, SLC1A5, KRAS mutation, colorectal cancer, amino acid transporters, glutamine transporter, cancer metabolism, depth of invasion, vascular invasion, cell migration, apoptosis, therapeutic target
- MeSH terms
- Aged, DNA Mutational Analysis, Female, Humans, Male, Mutation, Prognosis, Colorectal Neoplasms, Signal Transduction, Minor Histocompatibility Antigens, Proto-Oncogene Proteins p21(ras), Apoptosis, Amino Acid Transport System ASC, Cell Line, Tumor, Cell Proliferation, Kaplan-Meier Estimate, Gene Knockdown Techniques
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