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Induction of estrogen receptor β-mediated autophagy sensitizes breast cancer cells to TAD1822-7, a novel biphenyl urea taspine derivative

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Abstract

Background

Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor β (ERβ) can be potentially targeted for breast cancer therapy.

Methods and results

TAD1822-7 was evaluated for ERβ-mediated autophagy and cell death using cell proliferation assay, Annexin V/PI staining, immunofluorescence, western blotting, ERβ siRNA, ERβ plasmid transfection and hypoxia cell models. TAD1822-7 upregulated ERβ causing cell death and induced mitochondrial dysfunction and autophagy companied with mitochondrial located ERβ. Enhanced levels of microtubule associated protein1 light chain 3 (LC3)-II and p62/SQSTM1 (p62) indicated that TAD1822-7 blocked the late-stage autolysosome formation, leading to cell death. Mechanistically, TAD1822-7-induced cell death was mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Moreover, TAD1822-7 modulated hypoxia inducible factor (HIF) functions and autophagy via the inhibition of HIF-1β in the context of hypoxia-induced autophagy. ERβ overexpression and ERβ agonist showed similar effects, whereas ERβ siRNA abrogated TAD1822-7-induced cell death, the inhibition of PI3K/AKT pathway and autophagy. The involvement of PI3K/AKT pathway and autophagy was also demonstrated in TAD1822-7-treated hypoxic breast cancer cells.

Conclusions

These findings provide new insight into the mechanism underlying the inhibitory effects of TAD1822-7 via ERβ-mediated pathways in breast cancer cells.

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Data availability

The analyzed data are available from the corresponding author on reasonable request.

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (Grant Nos. 81773772 and no. 81903643) and the Fundamental Research Funds for the Central Universities.

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Contributions

Conceptualization: QS, YZ; Methodology: QW, KC; Formal analysis and investigation: QW, KC, JW, AS; Writing—original draft preparation: QS, YZ; Writing—review and editing: QS, YZ; Funding acquisition: QS, YZ; Resources: YZ; Supervision: YZ.

Corresponding author

Correspondence to Yanmin Zhang.

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The authors have no relevant financial or non-financial interests to disclose.

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Present study was conducted after the prior approval by the biomedical ethics committee of Xi'an Jiaotong University Health Science Center and conform to ethical principles.

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Su, Q., Wu, Q., Chen, K. et al. Induction of estrogen receptor β-mediated autophagy sensitizes breast cancer cells to TAD1822-7, a novel biphenyl urea taspine derivative. Mol Biol Rep 49, 1223–1232 (2022). https://doi.org/10.1007/s11033-021-06950-5

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