Slc1a5, also known as alanine-serine-cysteine transporter 2 (ASCT2), is a crucial neutral amino-acid exchanger and the most well-studied glutamine transporter [8]. Glutamine is an essential nutrient regulating energy production, redox homeostasis, and signaling. Slc1a5 is involved in processes like mitochondrial metabolism, amino-acid sensing, and activation of mTORC1, a key metabolic regulator [2,5].

In osteoclastogenesis, Slc1a5-deficient mice showed reduced glutamine uptake in bone marrow cells stimulated with RANKL. The formation of multinucleated osteoclasts was severely impaired in Slc1a5-/-bone marrow cells, and the expression of ERK, NFκB, p70S6K, and NFATc1 was suppressed, indicating its important role in osteoclast formation [8]. In cancer, a SLC1A5 variant was found to transport glutamine into mitochondria, mediating cancer metabolic reprogramming. Overexpression of this variant conferred gemcitabine resistance to pancreatic cancer cells, and its knockdown and overexpression altered cancer cell and tumor growth [1]. In melanoma, miR-137 negatively regulated ferroptosis by directly targeting SLC1A5, with miR-137 knockdown enhancing the antitumor activity of erastin both in vitro and in vivo [3]. In gastric cancer, quercetin induced ferroptosis by targeting SLC1A5, inhibiting the NRF2/xCT pathway, activating the p-Camk2/p-DRP1 pathway, and accelerating iron deposition [4]. In leukemia, the STAT3-MYC axis regulated SLC1A5, and inhibition of SLC1A5 reduced intracellular levels of glutamine, glutathione, and multiple TCA cycle metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS in leukemia stem cells [5]. In glioma, SLC1A5 knockdown inhibited cell proliferation, invasion, and reduced ferroptosis sensitivity via the GPX4-dependent pathway, and was related to immune response [6]. In hepatocellular carcinoma, lncRNA SLC1A5-AS regulated SLC1A5 expression, and overexpression of SLC1A5-AS increased ASCT2 levels, enhancing glutamine uptake and promoting HCC cell growth and metastasis [7]. In pancreatic adenocarcinoma, SLC1A5 overexpression promoted cancer cell proliferation, migration, and invasion, and was related to a poor prognosis and suppressed antitumor immune process [9]. In hepatocellular carcinoma, elevated SLC1A5 was associated with poor prognosis and resistance to transarterial chemoembolization, and SLC1A5 may mediate cell migration and drug resistance via the EMT pathway [10].

In conclusion, Slc1a5 plays essential roles in various biological processes, especially in osteoclast formation and cancer-related metabolism, ferroptosis, and immune-related processes. The use of gene-knockout models, such as the Slc1a5-deficient mice, has significantly contributed to understanding its functions in osteoclastogenesis. In the context of cancer, studies on SLC1A5 have provided insights into its role in metabolic reprogramming, ferroptosis regulation, and immune-tumor interactions, suggesting potential therapeutic targets for multiple cancers.

References:

1. Yoo, Hee Chan, Park, Seung Joon, Nam, Miso, Bang, Seungmin, Han, Jung Min. 2019. A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells. In Cell metabolism, 31, 267-283.e12. doi:10.1016/j.cmet.2019.11.020. https://pubmed.ncbi.nlm.nih.gov/31866442/

2. Nachef, Marianna, Ali, Alaa Kassim, Almutairi, Saeedah Musaed, Lee, Seung-Hwan. 2021. Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment. In Frontiers in immunology, 12, 624324. doi:10.3389/fimmu.2021.624324. https://pubmed.ncbi.nlm.nih.gov/33953707/

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5. Amaya, Maria L, Inguva, Anagha, Pei, Shanshan, Reigan, Philip, Jordan, Craig T. . The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation. In Blood, 139, 584-596. doi:10.1182/blood.2021013201. https://pubmed.ncbi.nlm.nih.gov/34525179/

6. Han, Liying, Zhou, Jinpeng, Li, Leiyang, Wang, Liang, Qu, Yan. 2022. SLC1A5 enhances malignant phenotypes through modulating ferroptosis status and immune microenvironment in glioma. In Cell death & disease, 13, 1071. doi:10.1038/s41419-022-05526-w. https://pubmed.ncbi.nlm.nih.gov/36566214/

7. Jiang, Jiawen, Dong, Wei, Zhang, Wen, Wang, Jiao, Li, Zhe. . LncRNA SLC1A5-AS/MZF1/ASCT2 Axis Contributes to Malignant Progression of Hepatocellular Carcinoma. In Discovery medicine, 35, 995-1014. doi:10.24976/Discov.Med.202335179.96. https://pubmed.ncbi.nlm.nih.gov/38058065/

8. Tsumura, Hideki, Shindo, Miyuki, Ito, Morihiro, Umezawa, Akihiro, Ito, Yasuhiko. 2021. Relationships between Slc1a5 and Osteoclastogenesis. In Comparative medicine, 71, 285-294. doi:10.30802/AALAS-CM-21-000012. https://pubmed.ncbi.nlm.nih.gov/34301346/

9. Xu, Fangshi, Wang, Hai, Pei, Honghong, Wang, Shuang, Ren, Bin-Cheng. 2022. SLC1A5 Prefers to Play as an Accomplice Rather Than an Opponent in Pancreatic Adenocarcinoma. In Frontiers in cell and developmental biology, 10, 800925. doi:10.3389/fcell.2022.800925. https://pubmed.ncbi.nlm.nih.gov/35419359/

10. Zhang, Guixiong, Xiao, Yitai, Tan, Jizhou, Fan, Wenzhe, Li, Jiaping. 2024. Elevated SLC1A5 associated with poor prognosis and therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma. In Journal of translational medicine, 22, 543. doi:10.1186/s12967-024-05298-1. https://pubmed.ncbi.nlm.nih.gov/38844930/