GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis.
GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis.
复制标题
GSTZ1通过抑制NRF2/GPX4轴，使肝癌细胞对索拉非尼诱导的铁死亡更加敏感。
DOI：
10.1038/s41419-021-03718-4
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发表时间：
2021-04-30
影响因子：
9
通讯作者：
Tang N
中科院分区：
文献类型：
--
作者：
Wang Q;Bin C;Xue Q;Gao Q;Huang A;Wang K;Tang N
越来越多的证据表明，铁死亡在抑制肿瘤生长中发挥着重要作用。索拉非尼最初被认定为多种致癌激酶的抑制剂，现已证实它可诱导肝细胞癌（HCC）发生铁死亡。然而，部分肝癌细胞系对索拉非尼诱导的铁死亡性细胞死亡不太敏感。谷胱甘肽S - 转移酶ζ1（GSTZ1）是苯丙氨酸分解代谢中的一种酶，它可抑制细胞氧化还原稳态的主要调节因子——核因子E2相关因子2（NRF2）的表达。本研究旨在探究GSTZ1在索拉非尼诱导的肝癌铁死亡中的作用及潜在分子机制。在索拉非尼耐药的肝癌细胞中，GSTZ1显著下调。从机制上讲，GSTZ1缺失增强了NRF2通路的激活，并提高了谷胱甘肽过氧化物酶4（GPX4）的水平，从而抑制了索拉非尼诱导的铁死亡。索拉非尼与GPX4抑制剂RSL3联合使用，可显著抑制GSTZ1缺陷细胞的活力，促进铁死亡，并增加异位铁和脂质过氧化物。在体内实验中，索拉非尼与RSL3联合使用对Gstz1−/−小鼠的肝癌进展具有协同治疗作用。总之，这一发现表明，GSTZ1通过抑制肝癌细胞中的NRF2/GPX4轴，增强了索拉非尼诱导的铁死亡。索拉非尼与GPX4抑制剂RSL3的联合治疗可能是一种有前景的肝癌治疗策略。
Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, suppresses the expression of the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role and underlying molecular mechanisms of GSTZ1 in sorafenib-induced ferroptosis in HCC. GSTZ1 was significantly downregulated in sorafenib-resistant hepatoma cells. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1-deficient cell viability and promoted ferroptosis and increased ectopic iron and lipid peroxides. In vivo, the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1−/− mice. In conclusion, this finding demonstrates that GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. Combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment.