Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells
Na-Yiyuan Wu,
Hsuan-Shun Huang,
Tung Hui Chao,
Hsien Ming Chou,
Chao Fang,
Chong-Zhen Qin,
Chueh-Yu Lin,
Tang-Yuan Chu,
Hong Hao Zhou
Affiliations
Na-Yiyuan Wu
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China
Hsuan-Shun Huang
Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC
Tung Hui Chao
Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC
Hsien Ming Chou
Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC
Chao Fang
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China
Chong-Zhen Qin
Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410078, People’s Republic of China
Chueh-Yu Lin
Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, ROC
Tang-Yuan Chu
Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC
Hong Hao Zhou
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China
High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells. Here we show that P4, via P4 receptors (PRs), induces necroptosis in Trp53−/− mouse oviduct epithelium and in immortalized human p53-defective fimbrial epithelium through the TNF-α/RIPK1/RIPK3/MLKL pathway. Necroptosis occurs specifically at diestrus, recovers at the proestrus phase of the estrus cycle, and can be augmented with P4 supplementation. These results reveal the mechanism of the well-known ability of progesterone to prevent ovarian cancer.
