1. Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells
- Author
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Chong-Zhen Qin, Chao Fang, Hong Hao Zhou, Hsuan-Shun Huang, Na-Yiyuan Wu, Chueh-Yu Lin, Hsien Ming Chou, Tang-Yuan Chu, and Tung Hui Chao
- Subjects
0301 basic medicine ,Apoptosis ,Oviducts ,progesterone receptor ,Epithelium ,Mice ,0302 clinical medicine ,Ovarian carcinoma ,DNA Breaks, Double-Stranded ,lcsh:QH301-705.5 ,Progesterone ,media_common ,Ovarian Neoplasms ,Serous fluid ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Receptors, Progesterone ,high-grade serous ovarian carcinoma ,Signal Transduction ,medicine.medical_specialty ,endocrine system ,Cell Survival ,media_common.quotation_subject ,Necroptosis ,necroptosis ,Estrous Cycle ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Necrosis ,Internal medicine ,Cell Line, Tumor ,Progesterone receptor ,medicine ,Animals ,Humans ,Ovulation ,Fallopian Tubes ,Epithelial Cells ,medicine.disease ,030104 developmental biology ,Endocrinology ,lcsh:Biology (General) ,Cancer research ,Neoplasm Grading ,Tumor Suppressor Protein p53 ,Ovarian cancer ,Neoplasms, Cystic, Mucinous, and Serous ,Fallopian tube - 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.
- Published
- 2016