Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Cell Biology | Enzymes and Coenzymes
Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of lipid-targeting reactive oxygen species that kill cells by damaging their plasma membrane. The lipid-repair enzyme glutathione peroxidase 4 (GPX4) protects against this oxidative damage and enables cells to resist ferroptosis. Recent work has revealed that matrix-detached carcinoma cells can be susceptible to ferroptosis and that they can evade this fate through the signaling properties of the alpha6beta4 integrin, which sustains GPX4 expression. Although these findings on ferroptosis are provocative, they differ from those in previous studies indicating that matrix-detached cells are prone to apoptosis, via a process referred to as anoikis. In an effort to reconcile these discrepant findings, here we observed that matrix-detached epithelial and carcinoma cells cluster spontaneously via a mechanism that involves the cell adhesion protein PVRL4 (also known as Nectin-4). We found that this clustering process allows these cells to survive by stimulating a PVRL4/alpha6beta4/Src signaling axis that sustains GPX4 expression and buffers against lipid peroxidation. In the absence of alpha6beta4, PVRL4-mediated clustering induced an increase in lipid peroxidation that was sufficient for triggering ferroptosis. When the clustering was inhibited, single cells did not exhibit a significant increase in lipid peroxidation in the absence of alpha6beta4, and they were more susceptible to apoptosis than to ferroptosis. These results indicate that ferroptosis induction depends on cell clustering in matrix-detached cells that lack alpha6beta4 and imply that the fate of matrix-detached cells can be determined by the state of their cell-cell interactions.
breast cancer, cell death, cell-cell interaction, extracellular matrix, ferroptosis, glutathione peroxidase 4, integrin, lipid peroxidation
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© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Article in press posted after 12 months as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/License%20to%20Publish_author%20retains%20ownership_v1_JBC.pdf.
DOI of Published Version
J Biol Chem. 2018 Jun 22. pii: jbc.RA118.003017. doi: 10.1074/jbc.RA118.003017. [Epub ahead of print]. Link to article on publisher's site
The Journal of biological chemistry
Brown CW, Amante JJ, Mercurio AM. (2018). Cell clustering mediated by the adhesion protein PVRL4 is necessary for alpha6beta4 integrin-promoted ferroptosis resistance in matrix-detached cells. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1074/jbc.RA118.003017. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1579