Frontiers in Pharmacology (Sep 2024)

Formononetin triggers ferroptosis in triple-negative breast cancer cells by regulating the mTORC1/SREBP1/SCD1 pathway

  • Dong Xie,
  • Dong Xie,
  • Yulang Jiang,
  • Yulang Jiang,
  • Huan Wang,
  • Lingyi Zhu,
  • Shuangqin Huang,
  • Sheng Liu,
  • Weihong Zhang,
  • Tian Li,
  • Tian Li

DOI
https://doi.org/10.3389/fphar.2024.1441105
Journal volume & issue
Vol. 15

Abstract

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IntroductionTriple-negative breast cancer (TNBC) is the most malignant type of breast cancer, and its prognosis is still the worst. It is necessary to constantly explore the pathogenesis and effective therapeutic targets of TNBC. Formononetin is an active ingredient with anti-tumor effects that we screened earlier. The main purpose of this study is to elucidate mechanism of the inhibitory effect of Formononetin on TNBC.MethodsWe conducted experiments through both in vivo and in vitro methodologies. The in vivo experiments utilized a nude mice xenotransplantation model, while the in vitro investigations employed two breast cancer cell lines, MDA-MB-231 and MDA-MB-468. Concurrently, ferroptosis associated proteins, lipid peroxide levels, and proteins related to the rapamycin complex 1 were analyzed in both experimental settings.ResultsIn our study, Formononetin exhibits significant inhibitory effects on the proliferation of triple TNBC, both in vivo and in vitro. Moreover, it elicits an increase in lipid peroxide levels, downregulates the expression of ferroptosis-associated proteins GPX4 and xCT, and induces ferroptosis in breast cancer cells. Concurrently, Formononetin impedes the formation of the mammalian target of rapamycin complex 1 (mTORC1) and suppresses the expression of downstream Sterol regulatory element-binding protein 1(SREBP1). The utilization of breast cancer cells with SREBP1 overexpression or knockout demonstrates that Formononetin induces ferroptosis by modulating the mTORC1-SREBP1 signaling axis.DiscussionIn conclusion, this study provides evidence that Formononetin exerts an anti-proliferative effect on triple-negative breast cancer by inducing ferroptosis. Moreover, the mTORC1-SREBP1 signal axis is identified as the primary mechanism through which formononetin exerts its therapeutic effects. These findings suggest that formononetin holds promise as a potential targeted drug for clinical treatment of TNBC.

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