Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen
BackgroundHonokiol (HON) inhibits epidermal growth factor receptor (EGFR) signaling and increases the activity of erlotinib, an EGFR inhibitor, in human head and neck cancers. In this study, using a bioinformatics approach and in vitro experiments, we assessed the target genes of HON against breast...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1019025/full |
| _version_ | 1828089896826306560 |
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| author | Adam Hermawan Adam Hermawan Adam Hermawan Herwandhani Putri Naufa Hanif Nurul Fatimah Heri Himawan Prasetio |
| author_facet | Adam Hermawan Adam Hermawan Adam Hermawan Herwandhani Putri Naufa Hanif Nurul Fatimah Heri Himawan Prasetio |
| author_sort | Adam Hermawan |
| collection | DOAJ |
| description | BackgroundHonokiol (HON) inhibits epidermal growth factor receptor (EGFR) signaling and increases the activity of erlotinib, an EGFR inhibitor, in human head and neck cancers. In this study, using a bioinformatics approach and in vitro experiments, we assessed the target genes of HON against breast cancer resistance to tamoxifen (TAM).Materials and methodsMicroarray data were obtained from GSE67916 and GSE85871 datasets to identify differentially expressed genes (DEGs). DEGs common between HON-treated and TAM-resistant cells were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and protein-protein interaction (PPI) networks were constructed. Selected genes were analyzed for genetic alterations, expression, prognostic value, and receiver operating characteristics (ROC). TAM-resistant MCF-7 (MCF-7 TAM-R) cells were generated and characterized for their resistance toward TAM. A combination of HON and TAM was used for cytotoxicity and gene expression analyses. Molecular docking was performed using the Molecular Operating Environment software.ResultsPPI network analysis revealed that FN1, FGFR2, and RET were the top three genes with the highest scores. A genetic alteration study of potential target genes revealed MMP16 and ERBB4 as the genes with the highest alterations among the breast cancer samples. Pathway enrichment analysis of FGFR2, RET, ERBB4, SOX2, FN1, and MMP16 showed that the genetic alterations herein were likely to impact the RTK-Ras pathway. The expression levels of RET, MMP16, and SOX2 were strongly correlated with prognostic power, with areas under the ROC curves (AUC) of 1, 0.8, and 0.8, respectively. The HON and TAM combination increased TAM cytotoxicity in MCF-7 TAM-R cells by regulating the expression of potential target genes ret, ERBB4, SOX2, and FN1, as well as the TAM resistance regulatory genes including HES1, VIM, PCNA, TP53, and CASP7. Molecular docking results indicated that HON tended to bind RET, ErbB4, and the receptor protein Notch1 ankyrin domain more robustly than its native ligand.ConclusionHON could overcome breast cancer resistance to TAM, potentially by targeting FGFR2, RET, ERBB4, MMP16, FN1, and SOX2. However, further studies are required to validate these results. |
| first_indexed | 2024-04-11T05:48:44Z |
| format | Article |
| id | doaj.art-4f9d40f6b30d40d3b0d2220d7ec3f0c0 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T05:48:44Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-4f9d40f6b30d40d3b0d2220d7ec3f0c02022-12-22T04:42:07ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-12-011210.3389/fonc.2022.10190251019025Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifenAdam Hermawan0Adam Hermawan1Adam Hermawan2Herwandhani Putri3Naufa Hanif4Nurul Fatimah5Heri Himawan Prasetio6Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, IndonesiaCancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, IndonesiaLaboratory of Advanced Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, IndonesiaCancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, IndonesiaCancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, IndonesiaLaboratory of Advanced Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, IndonesiaLaboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, IndonesiaBackgroundHonokiol (HON) inhibits epidermal growth factor receptor (EGFR) signaling and increases the activity of erlotinib, an EGFR inhibitor, in human head and neck cancers. In this study, using a bioinformatics approach and in vitro experiments, we assessed the target genes of HON against breast cancer resistance to tamoxifen (TAM).Materials and methodsMicroarray data were obtained from GSE67916 and GSE85871 datasets to identify differentially expressed genes (DEGs). DEGs common between HON-treated and TAM-resistant cells were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and protein-protein interaction (PPI) networks were constructed. Selected genes were analyzed for genetic alterations, expression, prognostic value, and receiver operating characteristics (ROC). TAM-resistant MCF-7 (MCF-7 TAM-R) cells were generated and characterized for their resistance toward TAM. A combination of HON and TAM was used for cytotoxicity and gene expression analyses. Molecular docking was performed using the Molecular Operating Environment software.ResultsPPI network analysis revealed that FN1, FGFR2, and RET were the top three genes with the highest scores. A genetic alteration study of potential target genes revealed MMP16 and ERBB4 as the genes with the highest alterations among the breast cancer samples. Pathway enrichment analysis of FGFR2, RET, ERBB4, SOX2, FN1, and MMP16 showed that the genetic alterations herein were likely to impact the RTK-Ras pathway. The expression levels of RET, MMP16, and SOX2 were strongly correlated with prognostic power, with areas under the ROC curves (AUC) of 1, 0.8, and 0.8, respectively. The HON and TAM combination increased TAM cytotoxicity in MCF-7 TAM-R cells by regulating the expression of potential target genes ret, ERBB4, SOX2, and FN1, as well as the TAM resistance regulatory genes including HES1, VIM, PCNA, TP53, and CASP7. Molecular docking results indicated that HON tended to bind RET, ErbB4, and the receptor protein Notch1 ankyrin domain more robustly than its native ligand.ConclusionHON could overcome breast cancer resistance to TAM, potentially by targeting FGFR2, RET, ERBB4, MMP16, FN1, and SOX2. However, further studies are required to validate these results.https://www.frontiersin.org/articles/10.3389/fonc.2022.1019025/fullhonokioltamoxifen resistancebreast cancerbioinformaticstargeted therapy |
| spellingShingle | Adam Hermawan Adam Hermawan Adam Hermawan Herwandhani Putri Naufa Hanif Nurul Fatimah Heri Himawan Prasetio Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen Frontiers in Oncology honokiol tamoxifen resistance breast cancer bioinformatics targeted therapy |
| title | Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen |
| title_full | Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen |
| title_fullStr | Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen |
| title_full_unstemmed | Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen |
| title_short | Identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen |
| title_sort | identification of potential target genes of honokiol in overcoming breast cancer resistance to tamoxifen |
| topic | honokiol tamoxifen resistance breast cancer bioinformatics targeted therapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1019025/full |
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