GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15

• Published in: Gynecologic oncology 2024-06, Vol.185, p.8-16
• Main Authors: Chang, Caroline, Cheng, Ya-Yun, Kamlapurkar, Shriya, White, Sierra, Tang, Priscilla W., Elhaw, Amal T., Javed, Zaineb, Aird, Katherine M., Mythreye, Karthikeyan, Phaëton, Rébécca, Hempel, Nadine
• Format: Article
• Language: English
• Subjects: Animals; Antioxidant enzymes; Cell Line, Tumor; Disease Progression; Female; GDF15; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; GPX3; Growth Differentiation Factor 15 - biosynthesis; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Humans; Metabolism; Mice; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2024.02.004

We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-β growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors. •GPX3 knock-down abrogates intraperitoneal tumor development in a syngeneic IP xenograft model of ovarian cancer.•GPX3 modulates pro-tumorigenic gene expression and regulates the TGF-β family member GDF15.•GPX3 expression correlates with regulatory T-cell and macrophage signatures, and PD-L1 expression in ovarian cancer.