Autophagy and cell death in breast cancer cells following oxidative stress by mitoquinone

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	FDA/CBER	OXIDSTRESS-3

Authors

• Y Gonzalez-Berrios
• E Shacter
• A Rao

Abstract

Mitoquinone, a mitochondrially-targeted redox-active agent, selectively killed breast cancer cells compared to healthy 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. Keap1, an oxidative stress sensor protein that regulates an antioxidant response via the transcription factor Nrf2, underwent oxidation, degradation, and dissociation from Nrf2 in drug-treated 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) and p62 proteins that are responsible for the formation and nucleation of the autophagy bodies. Autophagy was confirmed by ultrastructural analysis using electron microscopy and time-resolved FRET analysis of membrane-bound LC3-IIb. Our current experiments are focused on the link between mitoquinone-induced oxidative stress, specific protein oxidation, and autophagy as a primary cellular response.

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