Brown Caitlin W, Amante John J, Goel Hira Lal, Mercurio Arthur M
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA
J Cell Biol. 2017 Dec 4;216(12):4287-4297. doi: 10.1083/jcb.201701136. Epub 2017 Sep 28.
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 α6β4 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 α6β4. The mechanism that enables α6β4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, α6β4-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 α6β4 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 α6β4 is sufficient to trigger ferroptosis because GPX4 is suppressed. This causal link between α6β4 and ferroptosis has implications for cancer biology and therapy.
脂质过氧化增加可导致铁死亡，这是一种由谷胱甘肽过氧化物酶4（GPX4）抑制引发的细胞死亡形式，GPX4催化脂质过氧化物的还原，是铁死亡诱导剂（如埃拉斯汀）的作用靶点。α6β4整合素可保护贴壁上皮细胞和癌细胞免受埃拉斯汀诱导的铁死亡。此外，细胞外基质（ECM）脱离是铁死亡的生理触发因素，而α6β4可避免这种情况。α6β4逃避铁死亡的机制涉及其保护促铁死亡的膜脂质变化的能力。具体而言，α6β4介导的Src和STAT3激活可抑制ACSL4的表达，ACSL4是一种使膜富含长链多不饱和脂肪酸的酶，是铁死亡所必需的。缺乏α6β4的贴壁细胞需要诱导剂（如埃拉斯汀）才能发生铁死亡，因为尽管它们的ACSL4增加，但仍维持GPX4的表达。相比之下，缺乏α6β4的细胞的ECM脱离足以触发铁死亡，因为GPX4受到抑制。α6β4与铁死亡之间的这种因果关系对癌症生物学和治疗具有重要意义。
