Xpr1-KO Mouse

XPR1, also known as SLC53A1, is the only known human inorganic phosphate (Pi) exporter to date, playing an indispensable role in cellular Pi homeostasis [2]. Its function is crucial for numerous biological activities, and its dysfunction is associated with neurodegenerative disease [2]. XPR1 consists of an N-terminal SPX domain, a dimer-formation core domain and a Pi transport domain [2].

Genetic or pharmacologic inhibition of XPR1-dependent phosphate efflux leads to the toxic accumulation of intracellular phosphate in SLC34A2-high cancer cell lines, suggesting the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer [1]. In pancreatic β-cells, knockdown of XPR1 prevents the “phosphate flush” that accompanies stimulated insulin secretion, revealing XPR1 as the mediator of this process [3]. In epithelial ovarian cancer, knockdown of XPR1 induces growth arrest and apoptosis of ovarian clear cell carcinoma (OCCC) cells in vitro and inhibits the proliferation of xenografted OCCC cells in immunocompromised mice, indicating its critical role in OCCC tumorigenesis [4]. In hepatocellular carcinoma (HCC), silencing of XPR1 leads to decreased proliferation, migration, invasion, and colony formation, along with mitochondrial dysfunction and apoptosis [5].

In conclusion, XPR1 is essential for maintaining cellular phosphate homeostasis. Model-based research, especially loss-of-function experiments such as knockdown in various cell lines and xenograft mouse models, has revealed its significance in multiple disease conditions, including ovarian cancer, pancreatic β-cell function, epithelial ovarian cancer, and hepatocellular carcinoma. These findings suggest XPR1 as a potential therapeutic target in related diseases.

References:

1. Bondeson, Daniel P, Paolella, Brenton R, Asfaw, Adhana, Vazquez, Francisca, Golub, Todd R. 2022. Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer. In Nature cancer, 3, 681-695. doi:10.1038/s43018-022-00360-7. https://pubmed.ncbi.nlm.nih.gov/35437317/

2. Yan, Rui, Chen, Huiwen, Liu, Chuanyu, Gong, Jianke, Jiang, Daohua. 2024. Human XPR1 structures reveal phosphate export mechanism. In Nature, 633, 960-967. doi:10.1038/s41586-024-07852-9. https://pubmed.ncbi.nlm.nih.gov/39169184/

3. Barker, Christopher J, Tessaro, Fernando Henrique Galvão, Ferreira, Sabrina de Souza, Darè, Elisabetta, Berggren, Per-Olof. 2020. XPR1 Mediates the Pancreatic β-Cell Phosphate Flush. In Diabetes, 70, 111-118. doi:10.2337/db19-0633. https://pubmed.ncbi.nlm.nih.gov/32826297/

4. Akasu-Nagayoshi, Yoko, Hayashi, Tomoatsu, Kawabata, Ayako, Okamoto, Aikou, Akiyama, Tetsu. 2022. PHOSPHATE exporter XPR1/SLC53A1 is required for the tumorigenicity of epithelial ovarian cancer. In Cancer science, 113, 2034-2043. doi:10.1111/cas.15358. https://pubmed.ncbi.nlm.nih.gov/35377528/

5. Liao, Zi-Qiang, Lv, Yang-Feng, Kang, Mei-Diao, Yi, Yun, Tang, Qun. 2024. Inhibition of XPR1-dependent phosphate efflux induces mitochondrial dysfunction: A potential molecular target therapy for hepatocellular carcinoma? In Molecular carcinogenesis, 63, 2332-2345. doi:10.1002/mc.23812. https://pubmed.ncbi.nlm.nih.gov/39136583/