Ursolic acid inhibits the proliferation of triple‑negative breast cancer stem‑like cells through NRF2‑mediated ferroptosis

Yang,Xinhua; Yang,Xinhua; Liang,Beibei; Liang,Beibei; Zhang,Lisha; Zhang,Lisha; Zhang,Mingzhu; Zhang,Mingzhu; Ma,Ming; Ma,Ming; Qing,Lijuan; Qing,Lijuan; Yang,Hao; Yang,Hao; Huang,Gang; Huang,Gang; Zhao,Jian; Zhao,Jian

doi:10.3892/or.2024.8753

Ursolic acid inhibits the proliferation of triple‑negative breast cancer stem‑like cells through NRF2‑mediated ferroptosis

Authors:
- Xinhua Yang
- Beibei Liang
- Lisha Zhang
- Mingzhu Zhang
- Ming Ma
- Lijuan Qing
- Hao Yang
- Gang Huang
- Jian Zhao
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Affiliations: Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China, Shanghai Key Laboratory of Molecular Imaging, Jiading Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China, The Preparation Center, Nanchang Hongdu Hospital of TCM, Nanchang, Jiangxi 330013, P.R. China, School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, P.R. China, Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P.R. China
Published online on: June 6, 2024 https://doi.org/10.3892/or.2024.8753
Article Number: 94
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ursolic acid (UA), a pentacyclic triterpenoid that has been found in a broad variety of fruits, spices and medicinal plants, has various biological effects such as reducing inflammation, protecting cells from damage, and preserving brain function. However, its impact on ferroptosis in cancer stem‑like cells remains unexplored. The present study investigated the effect of UA on MDA‑MB‑231 and BT‑549 cell‑derived triple‑negative breast CSCs (BCSCs) and its potential ferroptosis pathway. The effects of ferroptosis on BCSCs were demonstrated by the detection of ferroptosis‑related indexes including the intracellular level of glutathione, malondialdehyde, reactive oxygen species and iron. The effects of UA on the biological behaviors of BCSCs were analyzed by Cell Counting Kit‑8, stemness indexes detection and mammosphere formation assay. The mechanism of UA induction on BCSCs was explored by reverse transcription‑quantitative PCR and western blotting. BALB/c‑nude mice were subcutaneously injected with MDA‑MB‑231‑derived BCSCs to establish xenograft models to detect the effects of UA in vivo. The results revealed that BCSCs have abnormal iron metabolism and are less susceptible to ferroptosis. UA effectively reduces the stemness traits and proliferation of BCSCs in spheroids and mice models by promoting ferroptosis. It was observed that UA stabilizes Kelch‑like ECH‑associated protein 1 and suppresses nuclear factor erythroid‑related factor 2 (NRF2) activation. These findings suggested that the ability of UA to trigger ferroptosis through the inhibition of the NRF2 pathway could be a promising approach for treating BCSCs, potentially addressing metastasis and drug resistance in triple‑negative breast cancer (TNBC). This expands the clinical applications of UA and provides a theoretical basis for its use in TNBC treatment.

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