Gpx3, glutathione peroxidase 3, is a selenoprotein and the only extracellular GPx in a family of oxidoreductases. It catalyzes the detoxification of hydro-and soluble lipid hydroperoxides by reduced glutathione, playing a crucial role in the antioxidant defense system [2]. It is involved in redox signaling and maintaining the balance of reactive oxygen species (ROS) levels in the extracellular tumor microenvironment and other biological contexts [2]. Genetic models, such as gene knockout (KO) mouse models, are valuable for studying its functions.

In cancer research, conditional knockout of Gpx3 in AT2 cells suppressed lung metastasis in spontaneous metastatic models, revealing a role of tumor-polarized Gpx3+ AT2 cells in promoting lung premetastatic niche formation [1]. In ovarian cancer, Gpx3 knockdown in ID8 cells abrogated clonogenicity and intraperitoneal tumor development in vivo, and loss of Gpx3 led to decreased gene expression patterns related to pro-tumorigenic signaling pathways, with GDF15 identified as strongly dependent on Gpx3 [4]. Also, Gpx3 knockdown in OVCAR3 cells inhibited clonogenicity and anchorage-independent cell survival, and Gpx3 was necessary for protecting cells from exogenous oxidant insult and for clonogenic survival in patient-derived ascites fluid [6]. In chicken cardiomyocytes, Gpx3 suppression significantly increased ROS levels, induced apoptosis, and was accompanied by autophagy [3]. In a murine model of pulmonary artery banding, Gpx3-deficient mice showed exacerbated maladaptive right ventricular remodeling and signs of right ventricular dysfunction [5].

In conclusion, Gpx3 is essential for antioxidant defense, and its dysregulation impacts various biological processes. KO/CKO mouse models have revealed its roles in cancer metastasis, tumor growth, cell survival under oxidative stress, and cardiac remodeling, highlighting its potential as a therapeutic target in cancer and cardiac diseases.

References:

1. Wang, Zixin, Zhu, Jie, Liu, Yanfang, Cao, Xuetao, Gu, Yan. 2022. Tumor-polarized GPX3+ AT2 lung epithelial cells promote premetastatic niche formation. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2201899119. doi:10.1073/pnas.2201899119. https://pubmed.ncbi.nlm.nih.gov/35914155/

2. Chang, Caroline, Worley, Beth L, Phaëton, Rébécca, Hempel, Nadine. 2020. Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer. In Cancers, 12, . doi:10.3390/cancers12082197. https://pubmed.ncbi.nlm.nih.gov/32781581/

3. Gong, Yafan, Yang, Jie, Cai, Jingzeng, Zhang, Jun Min, Zhang, Ziwei. 2018. Effect of Gpx3 gene silencing by siRNA on apoptosis and autophagy in chicken cardiomyocytes. In Journal of cellular physiology, 234, 7828-7838. doi:10.1002/jcp.27842. https://pubmed.ncbi.nlm.nih.gov/30515791/

4. Chang, Caroline, Cheng, Ya-Yun, Kamlapurkar, Shriya, Phaëton, Rébécca, Hempel, Nadine. 2024. GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15. In Gynecologic oncology, 185, 8-16. doi:10.1016/j.ygyno.2024.02.004. https://pubmed.ncbi.nlm.nih.gov/38342006/

5. Covington, Taylor A, Pilz, Patrick M, Mulhern, Ryan M, Fisch, Sudeshna, Grune, Jana. 2023. GPx3 deficiency exacerbates maladaptive right ventricular remodeling in experimental pulmonary artery banding. In American journal of physiology. Lung cellular and molecular physiology, 324, L550-L556. doi:10.1152/ajplung.00379.2022. https://pubmed.ncbi.nlm.nih.gov/36880685/

6. Worley, Beth L, Kim, Yeon Soo, Mardini, Jennifer, Aird, Katherine M, Hempel, Nadine. 2018. GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment. In Redox biology, 25, 101051. doi:10.1016/j.redox.2018.11.009. https://pubmed.ncbi.nlm.nih.gov/30509602/