High-adhesion ovarian cancer cell resistance to ferroptosis: The activation of NRF2/FSP1 pathway by junctional adhesion molecule JAM3

Ning Wang; Min Chen; Manting Wu; Yuan Liao; Qing Xia; Zheyou Cai; Chengsi He; Qing Tang; Yuan Zhou; Lei Zhao; Zhengzhi Zou; Yibing Chen; Liping Han

doi:10.1016/j.freeradbiomed.2024.12.040

High-adhesion ovarian cancer cell resistance to ferroptosis: The activation of NRF2/FSP1 pathway by junctional adhesion molecule JAM3

Free Radic Biol Med. 2024 Dec 18:S0891-5849(24)01149-3. doi: 10.1016/j.freeradbiomed.2024.12.040. Online ahead of print.

Authors

Ning Wang¹, Min Chen², Manting Wu², Yuan Liao³, Qing Xia⁴, Zheyou Cai⁵, Chengsi He⁵, Qing Tang⁵, Yuan Zhou⁵, Lei Zhao¹, Zhengzhi Zou⁶, Yibing Chen⁷, Liping Han⁸

Affiliations

¹ Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China.
² The Fourth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511300, China.
³ Department of Laboratory Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
⁴ Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
⁵ MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
⁶ MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China; Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, China. Electronic address: zouzhengzhi@m.scnu.edu.cn.
⁷ Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China. Electronic address: chenyibing@zzu.edu.cn.
⁸ Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China. Electronic address: fcchanlp@zzu.edu.cn.

PMID: 39706500
DOI: 10.1016/j.freeradbiomed.2024.12.040

Abstract

Ovarian cancer remains a significant challenge due to the lack of effective treatment and the resistance to conventional therapies. Ferroptosis, a form of regulated cell death characterized by iron-depend and lipid peroxidation, has emerged as a potential therapeutic target in cancer. Ovarian cancer has been reported to exert an "iron addiction" phenotype which makes it is susceptible to ferroptosis inducers. However, we found here that high-adhesion ovarian cancer cells were resistant to ferroptosis. Mechanistically, by PCR array, we identified junctional adhesion molecule 3 (JAM3) as a key mediator of ferroptosis resistance in high-adhesion ovarian cancer cells. Knockdowning and blocking JAM3 sensitized cancer cells to ferroptosis inducers RSL3 and erastin, while JAM3 overexpression conferred resistance to these agents. In addition, JAM3 also promoted ovarian cancer cells resistance to chemotherapeutic agent cisplatin in vitro and in vivo by inhibiting ferroptosis. Furthermore, we demonstrated that JAM3 promoted ferroptosis resistance through NRF2-induced upregulation of FSP1, a critical suppressor of lipid peroxidation. Inhibition of the NRF2/FSP1 pathway eliminated high-adhesion, JAM3 overexpressed ovarian cancer cells resistance to ferroptosis, and decreased cancer cells resistance to cisplatin. Moreover, JAM3 high expression was associated with poor prognosis in patients with ovarian cancer. Altogether, this study provided novel insights into the molecular mechanisms underlying ferroptosis resistance and identify JAM3 as a potential therapeutic target for combating drug resistance in ovarian cancer.

Keywords: Cell adhesion; FSP1; Ferroptosis; JAM3; Ovarian cancer.