2. Academic Validation
  3. Targeting PAX8 sensitizes ovarian cancer cells to ferroptosis by inhibiting glutathione synthesis

Targeting PAX8 sensitizes ovarian cancer cells to ferroptosis by inhibiting glutathione synthesis

  • Apoptosis. 2024 Jun 9. doi: 10.1007/s10495-024-01985-y.
Yanlin Luo # 1 2 3,  Xiaoli Liu # 4,  Yibing Chen # 5,  Qing Tang 3,  Chengsi He 3,  Xinyi Ding 3,  Jiachun Hu 3,  Zheyou Cai 3,  Xiang Li 6,  Hailing Qiao 7,  Zhengzhi Zou 8 9 10
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, School of Basic Medical Science, Zhengzhou University, Zhengzhou, 450001, China.
  • 2 Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, 450008, China.
  • 3 MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
  • 4 The Fourth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510631, China.
  • 5 Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.
  • 6 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 7 Institute of Clinical Pharmacology, School of Basic Medical Science, Zhengzhou University, Zhengzhou, 450001, China. qiaohl@zzu.edu.cn.
  • 8 MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China. zouzhengzhi@m.scnu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China. zouzhengzhi@m.scnu.edu.cn.
  • 10 Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China. zouzhengzhi@m.scnu.edu.cn.
  • # Contributed equally.
PMID: 38853202 DOI: 10.1007/s10495-024-01985-y
Abstract

Ovarian Cancer is a malignant tumor originating from the ovary, characterized by its high mortality rate and propensity for recurrence. In some patients, especially those with recurrent Cancer, conventional treatments such as surgical resection or standard chemotherapy yield suboptimal results. Consequently, there is an urgent need for novel anti-cancer therapeutic strategies. Ferroptosis is a distinct form of cell death separate from Apoptosis. Ferroptosis inducers have demonstrated promising potential in the treatment of ovarian Cancer, with evidence indicating their ability to enhance ovarian Cancer cell sensitivity to cisplatin. However, resistance of Cancer cells to Ferroptosis still remains an inevitable challenge. Here, we analyzed genome-scale CRISPR-Cas9 loss-of function screens and identified PAX8 as a Ferroptosis resistance protein in ovarian Cancer. We identified PAX8 as a susceptibility gene in GPX4-dependent ovarian Cancer. Depletion of PAX8 rendered GPX4-dependent ovarian Cancer cells significantly more sensitive to GPX4 inhibitors. Additionally, we found that PAX8 inhibited Ferroptosis in ovarian Cancer cells. Combined treatment with a PAX8 inhibitor and RSL3 suppressed ovarian Cancer cell growth, induced Ferroptosis, and was validated in a xenograft mouse model. Further exploration of the molecular mechanisms underlying PAX8 inhibition of Ferroptosis mutations revealed upregulation of glutamate-cysteine Ligase catalytic subunit (GCLC) expression. GCLC mediated the Ferroptosis resistance induced by PAX8 in ovarian Cancer. In conclusion, our study underscores the pivotal role of PAX8 as a therapeutic target in GPX4-dependent ovarian Cancer. The combination of PAX8 inhibitors such as losartan and captopril with Ferroptosis inducers represents a promising new approach for ovarian Cancer therapy.

Keywords

Ferroptosis; GCLC; GPX4; Ovarian cancer; PAX8.

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