Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis.
Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis.
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Metallothionein-1G 通过抑制铁死亡促进索拉非尼耐药。
DOI：
10.1002/hep.28574
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Tang D
中科院分区：
文献类型：
--
作者：
Sun X;Niu X;Chen R;He W;Chen D;Kang R;Tang D
肝细胞癌（HCC）是全球癌症相关死亡的主要原因，目前在所有癌症中发病率上升最快。索拉非尼最初被鉴定为多种致癌激酶的抑制剂，并且仍然是唯一被批准用于晚期HCC的全身治疗。然而，在肝癌患者中发现了对索拉非尼的获得性耐药，这导致预后不良。在这里，我们发现金属硫蛋白（MT）-1G是人肝癌细胞索拉非尼耐药的关键调节因子和有前途的治疗靶点。MT-1G的mRNA和蛋白质表达被索拉非尼显著诱导，而不是其他临床相关激酶抑制剂（例如，厄洛替尼、吉非替尼、tivantinib、维罗非尼、司美替尼、伊马替尼、马赛替尼和泊那替尼）。转录因子核因子红细胞2相关因子2（NRF 2）的激活，而不是p53和缺氧诱导因子1-α（HIF 1 α）的激活，是索拉非尼治疗后诱导MT-1G表达所必需的。重要的是，MT-1G的遗传和药理学抑制增强了索拉非尼在体外和肿瘤异种移植模型中的抗癌活性。MT-1G在索拉非尼耐药中作用的分子机制涉及抑制铁凋亡，一种新的调节性细胞死亡形式。通过RNAi敲低MT-1G增加谷胱甘肽耗竭和脂质过氧化，这有助于索拉非尼诱导的铁凋亡。这些发现表明索拉非尼耐药的一种新的分子机制，也表明MT-1G是肝癌细胞中铁凋亡的一种新的调节剂。
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide and currently has the fastest rising incidence of all cancers. Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the only approved systemic therapy for advanced HCC. However, acquired resistance to sorafenib has been found in HCC patients, which results in poor prognosis. Here, we showed that metallothionein (MT)-1G is a critical regulator and promising therapeutic target of sorafenib resistance in human HCC cells. The mRNA and protein expression of MT-1G is remarkably induced by sorafenib, but not other clinically-relevant kinase inhibitors (e.g., erlotinib, gefitinib, tivantinib, vemurafenib, selumetinib, imatinib, masitinib, and ponatinib). Activation of transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), but not p53 and hypoxia-inducible factor 1-alpha (HIF1α), is essential for induction of MT-1G expression following sorafenib treatment. Importantly, genetic and pharmacological inhibition of MT-1G enhances the anticancer activity of sorafenib in vitro and in tumor xenograft models. The molecular mechanisms underlying the action of MT-1G in sorafenib resistance involves the inhibition of ferroptosis, a novel form of regulated cell death. Knockdown of MT-1G by RNAi increases glutathione depletion and lipid peroxidation, which contributes to sorafenib-induced ferroptosis. These findings demonstrate a novel molecular mechanism of sorafenib resistance and also suggest that MT-1G is a new regulator of ferroptosis in HCC cells.