Slc1a5, also known as ASCT2, encodes a small neutral amino-acid exchanger and is a well-studied glutamine transporter. Glutamine is an essential nutrient for cancer cells, regulating energy production, redox homeostasis, and signaling. Slc1a5 is involved in multiple processes such as the mTORC1 signaling pathway, which promotes cell metabolism, and it also participates in sensing amino acid levels [2,6].

In osteoclastogenesis, Slc1a5-deficient mice showed reduced glutamine uptake in bone marrow cells stimulated with RANKL, and the formation of multinucleated osteoclasts was severely impaired. RANKL-induced expression of ERK, NFκB, p70S6K, and NFATc1 was suppressed in Slc1a5 -/- osteoclasts, indicating its important role in osteoclast formation [4]. In cancer, knockdown of Slc1a5 in various cancer cells led to decreased proliferation, colony formation, and migration, while increasing apoptosis and drug sensitivity. For example, in pancreatic cancer cells, overexpression of a SLC1A5 variant mediated glutamine-induced ATP production and glutathione synthesis, conferring gemcitabine resistance, and knockdown of SLC1A5 altered cancer cell and tumor growth, suggesting an oncogenic role [1,5,6]. In glioma, SLC1A5 knockdown inhibited cell proliferation, invasion, and reduced ferroptosis sensitivity via the GPX4-dependent pathway [3].

In conclusion, Slc1a5 is crucial for glutamine transport, playing important roles in biological processes like osteoclastogenesis and cancer-related events. Gene-knockout models, especially in mice, have significantly contributed to understanding its role in these areas, highlighting its potential as a therapeutic target in cancer treatment and for understanding bone-related disorders [1,3,4,5,6].

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/

3. 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/

4. 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/

5. 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/

6. 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/