Tau Aggregation‐Dependent Lipid Peroxide Accumulation Driven by the hsa_circ_0001546/14‐3‐3/CAMK2D/Tau Complex Inhibits Epithelial Ovarian Cancer Peritoneal Metastasis

Author:

Chai BinShu12,Wu Yong34,Yang HengHui1,Fan BiaoFeng1,Cao SiYu4,Zhang XiaoFei5,Xie YaQing1,Hu ZhiXiang6,Ma ZhongLiang2,Zhang YunKui7,Pan Wei2,Meng Wei2,Meng Jiao38,Tian WenJuan4,Zhang JiaLi8,Li YanLi2,Shao Yang38ORCID,Wang ShaoJia1

Affiliation:

1. Department of Gynecology The Third Affiliated Hospital of Kunming Medical University Yunnan Cancer Hospital Yunnan Cancer Center Kunming 650118 China

2. Lab for Noncoding RNA & Cancer School of Life Sciences Shanghai University Shanghai 200444 China

3. Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 China

4. Department of Gynecologic Oncology Fudan University Shanghai Cancer Center Shanghai 200032 China

5. Department of Gynecology Shanghai First Maternity and Infant Hospital Tongji University School of Medicine 2699 West Gaoke Road Shanghai 201204 China

6. Department of Integrative Oncology Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan University Shanghai 200032 China

7. Department of Anesthesiology Fudan University Shanghai Cancer Center Shanghai 200032 China

8. Cancer Institute Fudan University Shanghai Cancer Center, and Shanghai Fifth People's Hospital Shanghai 200032 China

Abstract

AbstractIntraperitoneal dissemination is the main method of epithelial ovarian cancer (EOC) metastasis, which is related to poor prognosis and a high recurrence rate. Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures that are implicated in the regulation of tumor development. In this study, hsa_circ_0001546 is downregulated in EOC primary and metastatic tissues vs. control tissues and this phenotype has a favorable effect on EOC OS and DFS. hsa_circ_0001546 can directly bind with 14‐3‐3 proteins to act as a chaperone molecule and has a limited positive effect on 14‐3‐3 protein stability. This complex recruits CAMK2D to induce the Ser324 phosphorylation of Tau proteins, changing the phosphorylation status of Tau bound to 14‐3‐3 and ultimately forming the hsa_circ_0001546/14‐3‐3/CAMK2D/Tau complex. The existence of this complex stimulates the production of Tau aggregation, which then induces the accumulation of lipid peroxides (LPOs) and causes LPO‐dependent ferroptosis. In vivo, treatment with ferrostatin‐1 and TRx0237 rescued the inhibitory effect of hsa_circ_0001546 on EOC cell spreading. Therefore, based on this results, ferroptosis caused by Tau aggregation occurs in EOC cells, which is not only in Alzheimer's disease‐ or Parkinson's disease‐related cells and this kind of ferroptosis driven by the hsa_circ_0001546/14‐3‐3/CAMK2D/Tau complex is LPO‐dependent rather than GPX4‐dependent is hypothesized.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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