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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Wu NY,Huang HS,Chao TH,Chou HM,Fang C,Qin CZ,Lin CY,Chu TY,Zhou HHdoi
10.1016/j.celrep.2017.02.049subject
Has Abstractpub_date
2017-03-14 00:00:00pages
2557-2565issue
11issn
2211-1247pii
S2211-1247(17)30247-4journal_volume
18pub_type
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