Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis
Abnormal expression of Forkhead box protein M1 (FOXM1) and serine/threonine kinase Budding uninhibited by benzimidazoles 1 (BUB1B) contributes to the development and progression of several cancers, including chronic myelogenous leukemia (CML). However, the molecular mechanism of the FOXM1/BUB1B regu...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.929996/full |
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| author | Shilpa Kuttikrishnan Shilpa Kuttikrishnan Tariq Masoodi Gulab Sher Ajaz A. Bhat Kalyani Patil Tamam El-Elimat Nicholas H. Oberlies Cedric J. Pearce Mohmmad Haris Mohmmad Haris Aamir Ahmad Aamir Ahmad Feras Q. Alali Shahab Uddin Shahab Uddin Shahab Uddin |
| author_facet | Shilpa Kuttikrishnan Shilpa Kuttikrishnan Tariq Masoodi Gulab Sher Ajaz A. Bhat Kalyani Patil Tamam El-Elimat Nicholas H. Oberlies Cedric J. Pearce Mohmmad Haris Mohmmad Haris Aamir Ahmad Aamir Ahmad Feras Q. Alali Shahab Uddin Shahab Uddin Shahab Uddin |
| author_sort | Shilpa Kuttikrishnan |
| collection | DOAJ |
| description | Abnormal expression of Forkhead box protein M1 (FOXM1) and serine/threonine kinase Budding uninhibited by benzimidazoles 1 (BUB1B) contributes to the development and progression of several cancers, including chronic myelogenous leukemia (CML). However, the molecular mechanism of the FOXM1/BUB1B regulatory network and the role of Neosetophomone-B (NSP-B) in leukemia remains unclear. NSP-B, a meroterpenoid fungal secondary metabolite, possesses anticancer potential in human leukemic cells lines; however, the underlying mechanism has not been elucidated. The present study aimed to explore the role of NSP-B on FOXM1/BUB1B signaling and the underlying molecular mechanism of apoptosis induction in leukemic cells. We performed gene expression profiling of NSP-B-treated and untreated leukemic cells to search for differentially expressed genes (DEGs). Interestingly BUB1B was found to be significantly downregulated (logFC -2.60, adjusted p = 0.001) in the treated cell line with the highest connectivity score among cancer genes. Analysis of TCGA data revealed overexpression of BUB1B compared to normal in most cancers and overexpression was associated with poor prognosis. BUB1B also showed a highly significant positive correlation with FOXM1 in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an in vitro study model to validate our findings. We found that NSP-B treatment of leukemic cells suppressed the expression of FOXM1 and BUB1B in a dose-dependent manner. In addition, NSP-B also resulted in the downregulation of FOXM1-regulated genes such as Aurora kinase A, Aurora kinase B, CDK4, and CDK6. Suppression of FOXM1 either by siRNA or NSP-B reduced BUB1B expression and enhanced cell survival inhibition and induction of apoptosis. Interestingly combination treatment of thiostrepton and NSP-B suppressed of cell viability and inducted apoptosis in leukemic cells via enhancing the activation of caspase-3 and caspase-8 compared with single-agent treatment. These results demonstrate the important role of the FOXM1/BUB1B pathway in leukemia and thus a potential therapeutic target. |
| first_indexed | 2024-12-12T12:22:03Z |
| format | Article |
| id | doaj.art-aa4fee98e0f0468ab766f80623ebb891 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-12T12:22:03Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-aa4fee98e0f0468ab766f80623ebb8912022-12-22T00:24:38ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.929996929996Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray AnalysisShilpa Kuttikrishnan0Shilpa Kuttikrishnan1Tariq Masoodi2Gulab Sher3Ajaz A. Bhat4Kalyani Patil5Tamam El-Elimat6Nicholas H. Oberlies7Cedric J. Pearce8Mohmmad Haris9Mohmmad Haris10Aamir Ahmad11Aamir Ahmad12Feras Q. Alali13Shahab Uddin14Shahab Uddin15Shahab Uddin16Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarCollege of Pharmacy, Qatar University, Doha, QatarLaboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, QatarTranslational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarLaboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, QatarTranslational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarDepartment of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, JordanDepartment of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, United StatesMycosynthetix, Inc., Hillsborough, NC, United StatesLaboratory of Molecular and Metabolic Imaging, Cancer Research Department, Sidra Medicine, Doha, QatarLaboratory of Animal Research Center, Qatar University, Doha, QatarTranslational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarDermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarCollege of Pharmacy, Qatar University, Doha, QatarTranslational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarLaboratory of Animal Research Center, Qatar University, Doha, QatarDermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, QatarAbnormal expression of Forkhead box protein M1 (FOXM1) and serine/threonine kinase Budding uninhibited by benzimidazoles 1 (BUB1B) contributes to the development and progression of several cancers, including chronic myelogenous leukemia (CML). However, the molecular mechanism of the FOXM1/BUB1B regulatory network and the role of Neosetophomone-B (NSP-B) in leukemia remains unclear. NSP-B, a meroterpenoid fungal secondary metabolite, possesses anticancer potential in human leukemic cells lines; however, the underlying mechanism has not been elucidated. The present study aimed to explore the role of NSP-B on FOXM1/BUB1B signaling and the underlying molecular mechanism of apoptosis induction in leukemic cells. We performed gene expression profiling of NSP-B-treated and untreated leukemic cells to search for differentially expressed genes (DEGs). Interestingly BUB1B was found to be significantly downregulated (logFC -2.60, adjusted p = 0.001) in the treated cell line with the highest connectivity score among cancer genes. Analysis of TCGA data revealed overexpression of BUB1B compared to normal in most cancers and overexpression was associated with poor prognosis. BUB1B also showed a highly significant positive correlation with FOXM1 in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an in vitro study model to validate our findings. We found that NSP-B treatment of leukemic cells suppressed the expression of FOXM1 and BUB1B in a dose-dependent manner. In addition, NSP-B also resulted in the downregulation of FOXM1-regulated genes such as Aurora kinase A, Aurora kinase B, CDK4, and CDK6. Suppression of FOXM1 either by siRNA or NSP-B reduced BUB1B expression and enhanced cell survival inhibition and induction of apoptosis. Interestingly combination treatment of thiostrepton and NSP-B suppressed of cell viability and inducted apoptosis in leukemic cells via enhancing the activation of caspase-3 and caspase-8 compared with single-agent treatment. These results demonstrate the important role of the FOXM1/BUB1B pathway in leukemia and thus a potential therapeutic target.https://www.frontiersin.org/articles/10.3389/fonc.2022.929996/fullfungal metabolitesNeosetophomone BFOXM1BUB1Bapoptosisleukemia |
| spellingShingle | Shilpa Kuttikrishnan Shilpa Kuttikrishnan Tariq Masoodi Gulab Sher Ajaz A. Bhat Kalyani Patil Tamam El-Elimat Nicholas H. Oberlies Cedric J. Pearce Mohmmad Haris Mohmmad Haris Aamir Ahmad Aamir Ahmad Feras Q. Alali Shahab Uddin Shahab Uddin Shahab Uddin Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis Frontiers in Oncology fungal metabolites Neosetophomone B FOXM1 BUB1B apoptosis leukemia |
| title | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis |
| title_full | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis |
| title_fullStr | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis |
| title_full_unstemmed | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis |
| title_short | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis |
| title_sort | bioinformatics analysis reveals foxm1 bub1b signaling pathway as a key target of neosetophomone b in human leukemic cells a gene network based microarray analysis |
| topic | fungal metabolites Neosetophomone B FOXM1 BUB1B apoptosis leukemia |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.929996/full |
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