Ribosome biogenesis mediates antitumor activity of flavopiridol in CD44+/CD24‑ breast cancer stem cells

Erol,Ayse; Acikgoz,Eda; Guven,Ummu; Duzagac,Fahriye; Turkkani,Ayten; Colcimen,Nese; Oktem,Gulperi

doi:10.3892/ol.2017.7029

Ribosome biogenesis mediates antitumor activity of flavopiridol in CD44+/CD24‑ breast cancer stem cells

Authors:
- Ayse Erol
- Eda Acikgoz
- Ummu Guven
- Fahriye Duzagac
- Ayten Turkkani
- Nese Colcimen
- Gulperi Oktem
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Affiliations: Department of Medical Pharmacology, School of Medicine, Ege University, 35100 Izmir, Turkey, Department of Histology and Embryology, School of Medicine, Yuzuncu Yil University, 65000 Van, Turkey, Department of Stem Cell, Institute of Health Sciences, Ege University, 35100 Izmir, Turkey, Department of Histology and Embryology, School of Medicine, TOBB University of Economics and Technology, 06560 Ankara, Turkey
Published online on: September 22, 2017 https://doi.org/10.3892/ol.2017.7029
Pages: 6433-6440
Copyright: © Erol et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Flavopiridol is a synthetically produced flavonoid that potently inhibits the proliferation of human tumor cell lines. Flavopiridol exerts strong antitumor activity via several mechanisms, including the induction of cell cycle arrest and apoptosis, and the modulation of transcriptional regulation. The aim of the present study was to determine the effect of flavopiridol on a subpopulation of cluster of differentiation (CD)44+/CD24‑ human breast cancer MCF7 stem cells. The CD44+/CD24‑ cells were isolated from the MCF7 cell line by fluorescence‑activated cell sorting and treated with 100, 300, 500, 750 and 1,000 nM flavopiridol for 24, 48 and 72 h. Cell viability and proliferation assays were performed to determine the inhibitory effect of flavopiridol. Gene expression profiling was analyzed using Illumina Human HT‑12 v4 Expression BeadChip microarray. According to the results, the half maximal inhibitory concentration (IC50) value of flavopiridol was 500 nM in monolayer cells. Flavopiridol induced growth inhibition and cytotoxicity in breast cancer stem cells (BCSCs) at the IC50 dose. The present study revealed several differentially regulated genes between flavopiridol‑treated and untreated cells. The result of the pathway analysis revealed that flavopiridol serves an important role in translation, the ribosome biogenesis pathway, oxidative phosphorylation, the electron transport chain pathway, carbon metabolism and cell cycle. A notable result from the present study is that ribosome‑associated gene expression is significantly affected by flavopiridol treatment. The data of the present study indicate that flavopiridol exhibits antitumor activity against CD44+/CD24‑ MCF7 BCSCs through different mechanisms, mainly by inhibiting translation and the ribosome biogenesis pathway, and could be an effective chemotherapeutic molecule to target and kill BCSCs.

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