Mechanism of Erastin-Induced Ferroptosis in MDA-MB-231 Human Breast Cancer Cells: Evidence for a Critical Role of Protein Disulfide Isomerase
Open Access
- 2 May 2022
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 42 (6), e0052221
- https://doi.org/10.1128/mcb.00522-21
Abstract
Ferroptosis is a form of regulated cell death resulting predominantly from catastrophic accumulation of lipid reactive oxygen species (ROS). While the antioxidant systems that counter ferroptosis have been well characterized, the mechanism underlying ferroptosis-associated accumulation of lipid ROS remains unclear. In this study, we demonstrated that protein disulfide isomerase (PDI) is a novel mediator of ferroptosis, which is responsible for the accumulation of lipid ROS and ultimately ferroptosis in MDA-MB-231 human breast cancer cells. Treatment with erastin led to a significant increase in inducible nitric oxide synthase (iNOS)-mediated nitric oxide production, which contributes to the accumulation of the death-inducing cellular lipid ROS. Small interfering RNA (siRNA)-mediated PDI knockdown or pharmacological inhibition of PDI's isomerase activity with cystamine strongly suppressed iNOS dimerization and its catalytic activation, subsequently prevented lipid ROS accumulation, and conferred strong protection against erastin-induced ferroptosis. Remarkably, PDI knockdown in MDA-MB-231 cells also largely abrogated the protective effect of cystamine against erastin-induced ferroptotic cell death. Together, these experimental observations demonstrate a noncanonical role of PDI in ferroptosis, which may serve as a potential therapeutic target for ferroptosis-related diseases. Ferroptosis is a form of regulated cell death resulting predominantly from catastrophic accumulation of lipid reactive oxygen species (ROS). While the antioxidant systems that counter ferroptosis have been well characterized, the mechanism underlying ferroptosis-associated accumulation of lipid ROS remains unclear. In this study, we demonstrated that protein disulfide isomerase (PDI) is a novel mediator of ferroptosis, which is responsible for the accumulation of lipid ROS and ultimately ferroptosis in MDA-MB-231 human breast cancer cells.Keywords
Funding Information
- National Natural Science Foundation of China (81630096)
- Shenzhen Bay Laboratory (SZB2019062801007)
- Shenzhen Human Resources and Social Security Bureau | Shenzhen Peacock Plan (KQTD2016053117035204)
- Shenzhen Municipal Science and Technology Innovation Council | Shenzhen Key Laboratory Fund (ZDSYS20190902093417963)
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