Salinomycin induces apoptosis and senescence in breast cancer: Upregulation of p21, downregulation of survivin and histone H3 and H4 hyperacetylation
المؤلف | Al Dhaheri, Yusra |
المؤلف | Attoub, Samir |
المؤلف | Arafat, Kholoud |
المؤلف | AbuQamar, Synan |
المؤلف | Eid, Ali |
المؤلف | Al Faresi, Nesreen |
المؤلف | Iratni, Rabah |
تاريخ الإتاحة | 2023-09-25T10:26:15Z |
تاريخ النشر | 2013 |
اسم المنشور | Biochimica et Biophysica Acta - General Subjects |
المصدر | Scopus |
الملخص | Background In the present study, we investigated the effect of Salinomycin on the survival of three human breast cancer cell lines MCF-7, T47D and MDA-MB-231 grown in adherent culture conditions. Methods Cell viability was measured by CellTiter-Glo and Trypan blue exclusion assay. Apoptosis was determined by caspase 3/7 activation, PARP cleavage and Annexin V staining. Cell cycle distribution was assessed by propidium iodide flow cytometry. Senescence was confirmed by measuring the senescence-associated β-galactosidase activity. Changes in protein expression and histone hyperacetylation was determined by western blot and confirmed by immunofluorescence assay. Results Salinomycinwas able to inhibit the growth of the three cell lines in time- and concentration-dependent manners. We showed that depending on the concentrations used, Salinomycin elicits different effects on theMDA-MB-231 cells. High concentrations of Salinomycin induced a G2 arrest, downregulation of survivin and triggered apoptosis. Interestingly, treatment with low concentrations of Salinomycin induced a transient G1 arrest at earlier time point and G2 arrest at later point and senescence associatedwith enlarged cellmorphology, upregulation of p21 protein, increase in histone H3 and H4 hyperacetylation and expression of SA-β-Gal activity. Furthermore, we found that Salinomycin was able to potentiate the killing of the MCF-7 and MDA-MB-231 cells, by the chemotherapeutic agents, 4-Hydroxytamoxifen and frondoside A, respectively. Conclusion Our data are the first to link senescence and histone modifications to Salinomycin. Significance This study provides a new insight to better understand the mechanism of action of Salinomycin, at least in breast cancer cells. |
راعي المشروع | This work was supported by the Faculty of Science interdisciplinary research grant UAE University and by the Emirates Foundation research grant (2009-80) to R. Iratni and by the Terry Fox fund for Cancer Research grant to S. Attoub. We thank Dr Ranjit Vijayan from the Department of Biology, Faculty of Science, UAE. University, Al-Ain, United Arab Emirates, for his precious help in statistical analysis, Prof. Thomas Adrian from the Department of Physiology, Faculty of Medicine & Health Sciences, UAE. University, Al-Ain, United Arab Emirates, and Mr. Peter Colin from Coastside Bio Resources, Stonington, US for providing Frondoside A. We also thank Prof. Joan Massague from Howard Hughes Medical Institute for providing the MDA-MB-231 cells and Dr. Olivier De Wever from the Laboratory of Experimental Cancer Research, Gent, Belgium for providing the T47D cells. |
اللغة | en |
الناشر | Elsevier |
الموضوع | Apoptosis DNA damage Histone hyperacetylation p21 Salinomycin Senescence-associated beta galactosidase (SA-β-Gal) |
النوع | Article |
الصفحات | 3121-3135 |
رقم العدد | 4 |
رقم المجلد | 1830 |
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