Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, Wang H, Cao L, Tang D
Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Oncogene. 2015 Nov 5;34(45):5617-25. doi: 10.1038/onc.2015.32. Epub 2015 Mar 2.
Ferroptosis is an iron-dependent form of non-apoptotic cell death, but its molecular mechanism remains largely unknown. Here, we demonstrate that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptotic cancer cell death. Erastin, a specific ferroptosis-inducing compound, stimulates heat shock factor 1 (HSF1)-dependent HSPB1 expression in cancer cells. Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. Protein kinase C-mediated HSPB1 phosphorylation confers protection against ferroptosis by reducing iron-mediated production of lipid reactive oxygen species. Moreover, inhibition of the HSF1-HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity of erastin in human xenograft mouse tumor models. Our findings reveal an essential role for HSPB1 in iron metabolism with important effects on ferroptosis-mediated cancer therapy.
铁死亡是一种铁依赖性的非凋亡性细胞死亡形式，但其分子机制仍 largely 未知。在此，我们证明热休克蛋白β-1（HSPB1）是铁死亡癌细胞死亡的负调节因子。埃拉斯汀是一种特异性诱导铁死亡的化合物，可刺激癌细胞中热休克因子1（HSF1）依赖性的HSPB1表达。敲低HSF1和HSPB1可增强埃拉斯汀诱导的铁死亡，而热休克预处理和HSPB1过表达则抑制埃拉斯汀诱导的铁死亡。蛋白激酶C介导的HSPB1磷酸化通过减少铁介导的脂质活性氧生成来赋予对铁死亡的保护作用。此外，在人异种移植小鼠肿瘤模型中，抑制HSF1-HSPB1途径和HSPB1磷酸化可增加埃拉斯汀的抗癌活性。我们的研究结果揭示了HSPB1在铁代谢中的重要作用，对铁死亡介导的癌症治疗具有重要影响。
