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A novel 8-hydroxyquinoline derivative induces breast cancer cell death through paraptosis and apoptosis

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Abstract

Chemotherapy represents one of the main conventional therapies for breast cancer. However, tumor cells develop mechanisms to evade chemotherapeutic-induced apoptosis. Thus, it is of great significance to induce non-apoptotic cell death modes, such as paraptosis, in breast cancer. Herein, a novel 8-hydroxyquinoline derivative, 5,7-dibromo-8-(methoxymethoxy)-2-methylquinoline (HQ-11), was obtained and its potential anti-breast cancer mechanisms were investigated. Our results showed that extensive cytoplasmic vacuoles derived from the endoplasmic reticulum (ER) and mitochondria were appeared in MCF7 and MDA-MB-231 breast cancer cells by HQ-11 incubation, and pretreatment of cycloheximide was able to inhibit this vacuolation and HQ-11-induced cell death, showing the characteristics of paraptosis. ER stress was involved in HQ-11-caused paraptosis evidenced by the increase of glucose-regulated protein 78, C/EBP homologous protein and polyubiquitinated proteins. Molecular docking analysis revealed a favorable binding mode of HQ-11 in the active site of the chymotrypsin-like β5 subunit of the proteasome, indicative of proteasome dysfunction under HQ-11 treatment, which might result in further aggravated ER stress. Furthermore, treatment of HQ-11 resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase, and inhibition of ERK with U0126 significantly attenuated HQ-11-induced ER stress and paraptosis. In addition, exposure to HQ-11 also caused apoptosis in breast cancer cells partially through activation of ERK pathway. All these results conclusively indicate that HQ-11 triggers two distinct cell death modes via inhibition of proteasome and activation of ERK pathway in breast cancer cells, providing a promising candidate in future anti-breast cancer therapy.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This project was supported by National Natural Science Foundation of China (Grant No. 81872449), Anhui Provincial Natural Science Foundation (Grant No. 2008085MH292), the Key Project of Natural Science Research of Universities in Anhui Province (Grant No. KJ2019A0055), and Key Program in the Youth Elite Support Plan in Universities of Anhui Province (Grant Nos. gxyqZD2019020 and gxyqZD2020016).

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Authors and Affiliations

  1. Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, 59 Hudong Road, Ma’anshan, 243002, Anhui, China

    Liang Ma, Xiaojing Xuan, Minghui Fan, Yumeng Zhang, Guozan Yuan, Guozheng Huang & Zi Liu

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  1. Liang Ma
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Contributions

LM and ZL conceived and planned the research. LM, XX, MF, YZ and ZL performed the experiment. LM and ZL analyzed the data. GY synthesized the compound HQ-11. LM and ZL wrote the main manuscript. LM, GH and ZL revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zi Liu.

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Ma, L., Xuan, X., Fan, M. et al. A novel 8-hydroxyquinoline derivative induces breast cancer cell death through paraptosis and apoptosis. Apoptosis 27, 577–589 (2022). https://doi.org/10.1007/s10495-022-01737-w

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