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Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in triple-negative breast cancer cellsстатья
Информация о цитировании статьи получена из
Web of Science,
Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 2 декабря 2020 г.
- Авторы: Chepikova Olga E., Malin Dmitry, Strekalova Elena, Lukasheva Elena V., Zamyatnin Andrey A., Cryns Vincent L.
- Журнал: Breast Cancer Research and Treatment
- Том: 183
- Номер: 3
- Год издания: 2020
- Издательство: Springer Nature
- Местоположение издательства: Switzerland
- Первая страница: 549
- Последняя страница: 564
- DOI: 10.1007/s10549-020-05801-4
- Аннотация: Purpose: Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood. Methods: Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO. Results: LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental differences between LO and lysine depletion. LO rapidly induces ROS with a return to baseline levels within 24 h that coincides temporally with induction of TXNRD activity, the rate-limiting enzyme in the thioredoxin antioxidant pathway. ROS induction is required for LO-mediated cell death and NRF2-dependent induction of TXNRD1. Silencing NRF2 or TXNRD1 enhances the cytotoxicity of LO. The pan-TXNRD inhibitor auranofin is synergistic with LO against transformed breast epithelial cells, but not untransformed cells, underscoring the tumor-selectivity of this strategy. Conclusions: LO exposes a redox vulnerability of TNBC cells to TXNRD inhibition by rendering tumor cells dependent on the thioredoxin antioxidant pathway for survival.
- Добавил в систему: Замятнин Андрей Александрович