Inhibition of Nicotinamide Phosphoribosyltransferase Induces Apoptosis in Estrogen Receptor-Positive MCF-7 Breast Cancer Cells

Mohammad Alaee; Shahnaz Khaghani; Kiarash Behroozfar; Zahra Hesari; Seyedeh Sara Ghorbanhosseini; Mitra Nourbakhsh

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자료유형: 학술저널

저자정보: Mohammad Alaee (Tehran University of Medical Sciences) Shahnaz Khaghani (Tehran University of Medical Sciences) Kiarash Behroozfar (Tehran University of Medical Sciences) Zahra Hesari (Iran University of Medical Sciences) Seyedeh Sara Ghorbanhosseini (Iran University of Medical Sciences) Mitra Nourbakhsh (Department of Biochemistry School of Medicine Iran University of Medical Sciences)

저널정보: 한국유방암학회 Journal of Breast Cancer Journal of Breast Cancer Vol.20 No.1

발행연도: 2017.1

수록면: 20 - 26 (7page)

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Tumor cells have increased turnover of nicotinamide adenine dinucleotide (NAD+), the main coenzyme in processes including adenosine diphosphate-ribosylation, deacetylation, and calcium mobilization. NAD+ is predominantly synthesized in human cells via the salvage pathway, with the first component being nicotinamide. Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in this pathway, and its chemical inhibition by FK866 has elicited antitumor effects in several preclinical models of solid and hematologic cancers. However, its efficacy in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2-positive breast cancer cells has not been previously investigated. In this study, we aimed to deplete the NAD+ content of MCF-7 cells, a model cell line for ER-positive breast cancer, by inhibiting NAMPT in order to evaluate downstream effects on p53 and its acetylation, p21 and Bcl- 2-associated X protein (BAX) expression, and finally, apoptosis in MCF-7 breast cancer cells. Methods: MCF-7 cells were cultured and treated with FK866. NAD+ levels in cells were determined colorimetrically. Levels of p53 and its acetylated form were determined by Western blotting. Expression of p21 and BAX was determined by real-time polymerase chain reaction. Finally, levels of apoptosis were assessed by flow cytometry using markers for annexin V and propidium iodide. Results: FK866 treatment was able to increase p53 levels and acetylation, upregulate BAX and p21 expression, and induce apoptosis in MCF-7 cells. Addition of exogenous NAD+ to cells reversed these effects, suggesting that FK866 exerted its effects by depleting NAD+ levels. Conclusion: Results showed that FK866 could effectively inhibit NAD+ biosynthesis and induce programmed cell death in MCF-7 cells, suggesting that NAMPT inhibitors may be useful for the treatment of ER-positive breast cancers.

참고문헌 (30)

참고문헌 신청

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Hasmann M / 2003 / FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis / Cancer Res 63:7436~7442

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