Journal
REDOX BIOLOGY
Volume 42, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2021.101928
Keywords
PARP; Ferroptosis; Lipid peroxidation; Ovarian cancer
Categories
Funding
- National Natural Science Foundation of China [81972836, 82003190]
- National Key R&D Program of China [2016YFC1303703]
- Hunan Province Key R&D Program Projects [2020SK2120]
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The study reveals that ferroptosis contributes to the efficacy of PARP inhibitor olaparib by downregulating SLC7A11 expression. Interference with ferroptosis leads to resistance to olaparib, while boosting ferroptosis enhances sensitivity to PARP inhibitors in BRCA-proficient ovarian cancer cells.
Pharmacologic inhibition of PARP is the primary therapeutic strategy for BRCA mutant ovarian cancer. However, most of patients carry wild-type BRCA1/2 with no significant clinical benefits from PARP inhibitors, calling for the needs to further understanding and developing new strategy when employing PARP inhibitors to treat ovarian cancer. Here, we show that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of PARP inhibitor olaparib. Mechanistically, pharmacological inhibition or genetic deletion of PARP downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Furthermore, ferroptosis perturbation results in significant resistance to olaparib without affecting DNA damage response, while boosting ferroptosis by ferroptosis inducers (FINs) synergistically sensitizes BRCA-proficient ovarian cancer cells and xenografts to PARP inhibitor. Together, our results reveal a previously unappreciated mechanism coupling ferroptosis to PARP inhibition and suggest the combination of PARP inhibitor and FINs in the treatment of BRCA-proficient ovarian cancer.
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