Paper
Abstract 1861: Autophagy and cell death in breast cancer cells following oxidative stress by mitoquinone.
Published Apr 15, 2013 · Yanira Gonzalez-Berrios, B. Aryal, Leena M. Chehab
Cancer Research
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Abstract
Mitoquinone (MitoQ), a mitochondrially-targeted redox-active ubiquinone agent, selectively killed breast cancer cells compared to healthy cells mammary epithelial cells. While mitoquinone treatment led to irreversible loss in clonogenicity, the exact mechanism by which this agent was cytotoxic was unknown. We demonstrated that mitoquinone, although a synthetic derivative of the antioxidant ubiquinone, generated superoxide in MDA-MB-231 cells. Investigation into the cytotoxicity mechanism of MitoQ showed that a greater number of cells undergo autophagy than apoptosis. Drug treatment increased protein levels of the autophagosome-associated light chain 3 (LC3-II) that is responsible for the formation and nucleation of the autophagy bodies. Autophagy was confirmed by ultrastructural analysis using electron microscopy. However, the relationship between mitoquinone-induced oxidative stress and autophagy as a primary cellular response was not clear. We found that MitoQ induces Atg7-dependent but Beclin-1-independent cellular autophagy. Cancer cells and mouse embryonic fibroblast (MEF) lacking the autophagy related gene 7 (Atg7) had lower levels of autophagy after MitoQ treatment than Atg7 wild-type counterparts. In addition, we observed higher levels of oxidation in Atg7 deficient cells. Keap1, an oxidative stress sensor protein that regulates an antioxidant response via the transcription factor Nrf2, underwent oxidation and degradation in drug-treated cells. However, in Atg7 deficient cells Keap1 degradation decreased, suggesting Atg7-dependent Keap1 degradation. Conversely, knockdown of Keap1 decreased autophagy levels, but had no apparent effect on apoptosis. In vivo studies using spontaneously hypertensive rats implanted with a tumor confirmed that treatment with MitoQ reduced tumor size and increase autophagy in tumor cells. We established the anti-tumor activity of Mito-Q in breast cancer cell lines and in an animal model. We also provided preliminary evidence for an Atg7- and Keap1- dependent autophagy as one of the mechanisms that respond to the oxidative stress by Mito-Q. Citation Format: Yanira Gonzalez-Berrios, Baikuntha P. Aryal, Leena M. Chehab, Ashutosh Rao. Autophagy and cell death in breast cancer cells following oxidative stress by mitoquinone. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1861. doi:10.1158/1538-7445.AM2013-1861
In Vitro StudyMitoquinone selectively kills breast cancer cells by inducing autophagy, a potential anti-tumor mechanism, and oxidative stress-dependent autophagy.
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