Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
Increases in lipid peroxidation can cause ferroptosis, a form of cell death triggered by inhibition of glutathione peroxidase 4 (GPX4), which catalyzes the reduction of lipid peroxides and is a target of ferroptosis inducers, such as erastin. The alpha6beta4 integrin protects adherent epithelial and carcinoma cells from ferroptosis induced by erastin. In addition, extracellular matrix (ECM) detachment is a physiologic trigger of ferroptosis, which is evaded by alpha6beta4. The mechanism that enables alpha6beta4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, alpha6beta4-mediated activation of Src and STAT3 suppresses expression of ACSL4, an enzyme that enriches membranes with long polyunsaturated fatty acids and is required for ferroptosis. Adherent cells lacking alpha6beta4 require an inducer, such as erastin, to undergo ferroptosis because they sustain GPX4 expression, despite their increase in ACSL4. In contrast, ECM detachment of cells lacking alpha6beta4 is sufficient to trigger ferroptosis because GPX4 is suppressed. This causal link between alpha6beta4 and ferroptosis has implications for cancer biology and therapy.
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© 2017 Brown et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
DOI of Published Version
J Cell Biol. 2017 Dec 4;216(12):4287-4297. doi: 10.1083/jcb.201701136. Epub 2017 Sep 28. Link to article on publisher's site
Journal of cell biology
Brown, Caitlin W.; Amante, John J.; Goel, Hira Lal; and Mercurio, Arthur M., "The alpha6beta4 integrin promotes resistance to ferroptosis" (2017). UMass Metabolic Network Publications. 135.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.