title: Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China; Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410078, People's Republic of China; Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, ROC.
authors.forename: Na-Yiyuan
authors.initials: NY
authors.lastname: Wu
authors.affiliation: Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC.
authors.forename: Hsuan-Shun
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC.
authors.forename: Tung Hui
authors.initials: TH
authors.lastname: Chao
authors.affiliation: Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC.
authors.forename: Hsien Ming
authors.initials: HM
authors.lastname: Chou
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410078, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.affiliation: Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410078, People's Republic of China; Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, People's Republic of China.
authors.forename: Chong-Zhen
authors.initials: CZ
authors.lastname: Qin
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, ROC; Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan, ROC.
authors.forename: Chueh-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Research, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC; Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan, ROC; Department of Obstetrics and Gynecology, Tzu Chi General Hospital, Hualien 970, Taiwan, ROC. Electronic address: hidrchu@gmail.com.
authors.forename: Tang-Yuan
authors.initials: TY
authors.lastname: Chu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, People's Republic of China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 410078, People's Republic of China. Electronic address: hhzhou2003@163.com.
authors.forename: Hong Hao
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D030762:Estrous Cycle / Q000187:drug effects; D005187:Fallopian Tubes / Q000473:pathology*; D005260:Female; D006801:Humans; D051379:Mice; D009336:Necrosis; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology* / Q000517:prevention & control*; D010057:Oviducts / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; D011374:Progesterone
keywords: high-grade serous ovarian carcinoma; necroptosis; progesterone; progesterone receptor