Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1.
Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1.
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DOI：
10.1016/j.apsb.2021.03.036
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Tao W
中科院分区：
文献类型：
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作者：
Kong N;Chen X;Feng J;Duan T;Liu S;Sun X;Chen P;Pan T;Yan L;Jin T;Xiang Y;Gao Q;Wen C;Ma W;Liu W;Zhang M;Yang Z;Wang W;Zhang R;Chen B;Xie T;Sui X;Tao W
铁凋亡是一种由铁积累和随后的脂质过氧化引起的非凋亡调节的细胞死亡。目前，铁下垂对癌症的治疗作用越来越受到关注。黄芩苷是黄芩中的有效成分，具有抗癌多种癌症的潜力；然而，黄芩素对膀胱癌的作用及其潜在的分子机制仍不清楚。本研究探讨了黄芩苷对膀胱癌细胞5637和KU-19-19的影响。结果表明，黄芩苷通过诱导膀胱癌细胞凋亡和细胞死亡发挥其抗癌作用。随后，我们首次在体外和体内证实了黄芩苷诱导的铁致细胞死亡，并伴有活性氧（ROS）的积累和细胞内螯合铁的富集。铁下垂抑制剂去铁胺拯救了黄芩苷诱导的细胞死亡，而坏死他汀-1、氯喹（CQ）、n-乙酰-l-半胱氨酸、l-谷胱甘肽还原或carbobenzoxy-valyl-alanyl-天冬氨酸-[o -甲基]-氟甲基酮（Z-VAD-FMK）却没有，这表明铁下垂有助于黄芩苷诱导的细胞死亡。在机制上，我们发现铁蛋白重链1 （FTH1）是黄芩苷诱导铁下垂的关键决定因素。在5637和KU19-19细胞中，过表达FTH1可消除黄芩苷的抗癌作用。综上所述，我们的数据首次提示天然产物黄芩苷通过诱导fth1依赖性铁凋亡发挥其抗癌活性，有望为膀胱癌治疗提供一个有前景的化合物。黄芩苷通过诱导铁蛋白重链1 （FTH1）依赖性铁下垂在膀胱癌中发挥抗癌作用，有望为膀胱癌的治疗提供巨大的治疗潜力。
Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on cancer is gaining increasing interest. Baicalin an active component in Scutellaria baicalensis Georgi with anticancer potential various cancer types; however, the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown. In the study, we investigated the effect of baicalin on bladder cancer cells 5637 and KU-19-19. As a result, we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells. Subsequently, we for the first time demonstrate baicalin-induced ferroptotic cell death in vitro and in vivo, accompanied by reactive oxygen species (ROS) accumulation and intracellular chelate iron enrichment. The ferroptosis inhibitor deferoxamine but not necrostatin-1, chloroquine (CQ), N-acetyl-l-cysteine, l-glutathione reduced, or carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK) rescued baicalin-induced cell death, indicating ferroptosis contributed to baicalin-induced cell death. Mechanistically, we show that ferritin heavy chain 1 (FTH1) was a key determinant for baicalin-induced ferroptosis. Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells. Taken together, our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis, which will hopefully provide a prospective compound for bladder cancer treatment. Baicalin exerts its anticancer activity in bladder cancer by inducing ferritin heavy chain 1 (FTH1)-dependent ferroptosis, which will hopefully provide great therapeutic potential for bladder cancer treatment.