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Updated: Jun 26, 2025
Isolation and Functional Assessment of Human Breast Cancer Stem Cells from Cell and Tissue Samples
Published on: October 2, 2020
Nobiletin Inhibits Breast Cancer Stem Cell by Regulating the Cell Cycle: A Comprehensive Bioinformatics Analysis and
Adam Hermawan1,2,3, Muthi Ikawati1,2, Dyaningtyas Dewi Pamungkas Putri2,3,4
1Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, Indonesia.
Abstract:
Inhibiting breast cancer stem cell (BCSC) signaling pathways is a strategic method for successfully treating breast cancer. Nobiletin (NOB) is a compound widely found in orange peel that exhibits a toxic effect on various types of cancer cells, and inhibits the signaling pathways that regulate the properties of BCSCs; however, the effects of NOB on BCSCs remain elusive. The purpose of this study was to determine the target genes of NOB for inhibiting BCSCs using in vitro three-dimensional breast cancer cell culture (mammospheres) and in silico approaches. We combined in vitro experiments to develop mammospheres and conducted cytotoxicity, next-generation sequencing, and bioinformatics analyses, such as gene ontology, the Reactome pathway enrichment, network topology, gene set enrichment analysis, hub genes selection, genetic alterations, prognostic value related to the mRNA expression, and mRNA and protein expression of potential NOB target genes that inhibit BCSCs. Here, we show that NOB inhibited BCSCs in mammospheres from MCF-7 cells. We also identified CDC6, CHEK1, BRCA1, UCHL5, TOP2A, MTMR4, and EXO1 as potential NOB targets inhibiting BCSCs. NOB decreased G0/G1, but increased the G2/M cell population. These findings showed that NOB is a potential therapeutic candidate for BCSCs treatment by regulating cell cycle.
Insights
Nobiletin (NOB) effectively inhibits breast cancer stem cells (BCSCs) by targeting key genes like CDC6 and CHEK1. This natural compound shows potential for breast cancer treatment by regulating the cell cycle.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Targeting breast cancer stem cells (BCSCs) is crucial for effective breast cancer treatment.
- Nobiletin (NOB), a natural compound from orange peel, shows anti-cancer properties but its effect on BCSCs is not well understood.
Purpose of the Study:
- To identify Nobiletin's target genes responsible for inhibiting BCSCs.
- To investigate NOB's mechanism of action on BCSCs using in vitro and in silico methods.
Main Methods:
- Utilized 3D mammosphere cultures and MCF-7 cells for in vitro studies.
- Employed next-generation sequencing and bioinformatics analyses including gene ontology, pathway enrichment, and network analysis.
- Validated target gene expression at mRNA and protein levels.
Main Results:
- Nobiletin demonstrated significant inhibition of BCSCs in mammosphere cultures.
- Identified CDC6, CHEK1, BRCA1, UCHL5, TOP2A, MTMR4, and EXO1 as potential NOB target genes.
- Observed NOB's effect on cell cycle, decreasing G0/G1 and increasing G2/M populations.
Conclusions:
- Nobiletin is a promising therapeutic candidate for targeting BCSCs.
- NOB exerts its effects by regulating cell cycle progression and targeting specific genes involved in BCSC properties.
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