The ?6?4 integrin promotes resistance to ferroptosis.

ABSTRACT: 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 ?6?4 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 ?6?4. The mechanism that enables ?6?4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, ?6?4-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 ?6?4 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 ?6?4 is sufficient to trigger ferroptosis because GPX4 is suppressed. This causal link between ?6?4 and ferroptosis has implications for cancer biology and therapy.

SUBMITTER: Brown CW 

PROVIDER: S-EPMC5716272 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature