Ferroptosis is a lysosomal cell death process
Ferroptosis is a lysosomal cell death process
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铁死亡是一种溶酶体细胞死亡过程
DOI：
10.1016/j.bbrc.2018.07.078
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发表时间：
2018-09-10
影响因子：
3.1
通讯作者：
Dai, Enyong
中科院分区：
文献类型：
--
作者：
Gao, Huan;Bai, Yuansong;Dai, Enyong
铁凋亡是一种由铁积累和脂质过氧化引起的调节性细胞死亡形式。虽然受损的铁凋亡与人类疾病和病症密切相关，但铁凋亡的机制和调节在很大程度上仍然未知。在这里，我们证明了STAT 3是人胰腺导管腺癌（PDAC）细胞系中铁凋亡的正调节因子。在erastin诱导的铁凋亡中，STAT 3的激活需要MAPK/ERK通路的激活，而不是Xc（-）系统的抑制。重要的是，通过小分子（例如，隐丹参酮和S31-201）或siRNA阻断erastin诱导的PDAC细胞中的铁凋亡。从机制上讲，STAT 3介导的组织蛋白酶B表达是铁凋亡所必需的。因此，通过药理学阻断组织蛋白酶活性（使用CA-074 Me）或空泡型H+-ATP酶（使用巴弗洛霉素A1）抑制溶酶体依赖性细胞死亡限制了erastin诱导的铁凋亡。这些研究表明，铁凋亡是一个溶酶体细胞死亡的过程。(C)2018爱思唯尔公司All rights reserved.
Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. While impaired ferroptosis is tightly linked to human diseases and conditions, the mechanism and regulation of ferroptosis remain largely unknown. Here, we demonstrate that STAT3 is a positive regulator of ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cell lines. Activation of the MAPK/ERK pathway, but not inhibition of system Xc(-), was required for STAT3 activation during erastin-induced ferroptosis. Importantly, pharmacological inhibition and genetic silencing of STAT3 through small molecules (e.g., cryptotanshinone and S31-201) or siRNA blocked erastin-induced ferroptosis in PDAC cells. Mechanically, STAT3-mediated cathepsin B expression was required for ferroptosis. Consequently, inhibition of lysosome-dependent cell death by pharmacological blockade of cathepsin activity (using CA-074Me) or vacuolar type H+-ATPase (using bafilomycin A1) limited erastin-induced ferroptosis. These studies indicate that ferroptosis is a lysosomal cell death process. (C) 2018 Elsevier Inc. All rights reserved.