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Cell Death Differ. 2019 Mar;26(3):502-515. doi: 10.1038/s41418-018-0151-2. Epub 2018 Jul 9.

Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies.

Author information

1
Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. so-youn-kim@northwestern.edu.
2
Department of Cancer Biology and Genetics, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
3
Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
4
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
5
Department of Cancer Biology and Genetics, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. takeshi.kurita@osumc.edu.

Abstract

Platinum-based chemotherapies can result in ovarian insufficiency by reducing the ovarian reserve, a reduction believed to result from apoptosis of immature oocytes via activation/phosphorylation of TAp63α by multiple kinases including CHEK2, CK1, and ABL1. Here we demonstrate that cisplatin (CDDP) induces oocyte apoptosis through a novel pathway and that temporary repression of this pathway fully preserves ovarian function in vivo. Although ABL kinase inhibitors effectively block CDDP-induced apoptosis of oocytes, oocytic ABL1, and ABL2 are dispensable for damage-induced apoptosis. Instead, CDDP activates TAp63α through the ATR > CHEK1 pathway independent of TAp63α hyper-phosphorylation, whereas X-irradiation activates the ATM > CHEK2 > TAp63α-hyper-phosphorylation pathway. Furthermore, oocyte-specific deletion of Trp73 partially protects oocytes from CDDP but not from X-ray, highlighting the fundamental differences of two pathways. Nevertheless, temporary repression of DNA damage response by a kinase inhibitor that attenuates phosphorylation of ATM, ATR, CHEK1, and CHEK2 fully preserves fertility in female mice against CDDP as well as X-ray. Our current study establishes the molecular basis and feasibility of adjuvant therapies to protect ovarian function against two distinctive gonadotoxic therapeutics, CDDP, and ionizing radiation.

PMID:
29988075
PMCID:
PMC6370889
[Available on 2020-03-01]
DOI:
10.1038/s41418-018-0151-2

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