Sculponeatin A promotes the ETS1-SYVN1 interaction to induce SLC7A11/xCT-dependent ferroptosis in breast cancer,Phytomedicine

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Sculponeatin A promotes the ETS1-SYVN1 interaction to induce SLC7A11/xCT-dependent ferroptosis in breast cancer
Phytomedicine ( IF 6.7 ) Pub Date : 2023-06-08 , DOI: 10.1016/j.phymed.2023.154921
Peng Peng ₁ , Yuliang Ren ₂ , Fang Wan ₂ , Miao Tan ₃ , Hui Wu ₄ , Jie Shen ₃ , Chen Qian ₄ , Xuewen Liu ₄ , Yuchen Xiang ₃ , Qingqing Yu ₅ , Liang Zhang ₆ , Yuan Si ₇ , Ying Liu ₇

Affiliation

Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei, China.
Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei, China.
Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Laboratory of Molecular Target Therapy of Cancer, Biomedical Research Institute, Hubei University of Medicine, Shiyan, Hubei, China.
Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China; Laboratory of Molecular Target Therapy of Cancer, Biomedical Research Institute, Hubei University of Medicine, Shiyan, Hubei, China.
Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China; Laboratory of Molecular Target Therapy of Cancer, Biomedical Research Institute, Hubei University of Medicine, Shiyan, Hubei, China.
Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei, China; Laboratory of Molecular Target Therapy of Cancer, Biomedical Research Institute, Hubei University of Medicine, Shiyan, Hubei, China.
Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, Hubei, China; Laboratory of Molecular Target Therapy of Cancer, Biomedical Research Institute, Hubei University of Medicine, Shiyan, Hubei, China.

Background

E26 transformation specificity-1 (ETS1) is a transcription factor that is overexpressed in breast cancer (BC) and promotes tumor progression. Sculponeatin A (stA), a new diterpenoid extracted from Isodon sculponeatus, has no reported antitumor mechanism.

Purpose

Here, we explored the antitumor activity of stA in BC and further clarified its mechanism.

Methods

Ferroptosis was detected by flow cytometric, glutathione, malondialdehyde, and iron determination assays. The effect of stA on the upstream signaling pathway of ferroptosis was detected by Western blot, gene expression, gene alterations and other approaches. The binding of stA and ETS1 was examined through a microscale thermophoresis assay and a drug affinity responsive target stability assay. An in vivo mouse model experiment was performed to evaluate the therapeutic and potential mechanism of stA.

Results

stA exhibits therapeutic potential in BC by inducing SLC7A11/xCT-dependent ferroptosis. stA decreases the expression of ETS1, which is responsible for xCT-dependent ferroptosis in BC. stA inhibits the transcriptional expression of xCT by directly binding to the ETS domain of the ETS1 protein. In addition, stA promotes proteasomal degradation of ETS1 by triggering ubiquitin ligase synoviolin 1 (SYVN1)-mediated ubiquitination. The K318 site of ETS1 mediates ubiquitination of ETS1 by SYVN1. In a mouse model, stA inhibits tumor growth without causing obvious toxicity.

Conclusion

Taken together, the results confirm that stA promotes the ETS1-SYVN1 interaction to induce ferroptosis in BC mediated by ETS1 degradation. stA is expected to be used in research of candidate drugs for BC and drug design based on ETS1 degradation.

中文翻译：

Sculponeatin A 促进 ETS1-SYVN1 相互作用以诱导乳腺癌中 SLC7A11/xCT 依赖性铁死亡

背景

E26 transformation specificity-1 (ETS1) 是一种在乳腺癌 (BC) 中过表达并促进肿瘤进展的转录因子。Sculponeatin A (stA) 是一种新的二萜类化合物，是从剑兰中提取的，目前尚无抗肿瘤机制的报道。

目的

在这里，我们探讨了 stA 在 BC 中的抗肿瘤活性，并进一步阐明了其机制。

方法

通过流式细胞仪、谷胱甘肽、丙二醛和铁测定法检测铁死亡。通过Western blot 、基因表达、基因改变等方法检测stA对铁死亡上游信号通路的影响。stA 和 ETS1 的结合通过微型热泳测定和药物亲和反应靶稳定性测定进行了检查。进行体内小鼠模型实验以评估 stA 的治疗和潜在机制。

结果

stA 通过诱导 SLC7A11/xCT 依赖性铁死亡在 BC 中表现出治疗潜力。stA 降低 ETS1 的表达，ETS1 是 BC 中 xCT 依赖性铁死亡的原因。stA通过直接结合ETS1 蛋白的ETS 结构域来抑制xCT的转录表达。此外，stA 通过触发泛素连接酶 synoviolin 1 (SYVN1) 介导的泛素化促进 ETS1 的蛋白酶体降解。ETS1 的 K318 位点介导 SYVN1 对 ETS1 的泛素化。在小鼠模型中，stA 抑制肿瘤生长而不会引起明显的毒性。