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.
Keywords: 8-Hydroxyquinoline derivative; Apoptosis; Breast cancer; ER stress; ERK; Paraptosis.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.