Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis
<p>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/B...
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2022
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| _version_ | 1864513529031163904 |
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| author | Shilpa Kuttikrishnan (3520079) |
| author2 | Tariq Masoodi (8117702) Gulab Sher (12984698) Ajaz A. Bhat (158004) Kalyani Patil (2679424) Tamam El-Elimat (694398) Nicholas H. Oberlies (16036193) Cedric J. Pearce (16036196) Mohmmad Haris (12984704) Aamir Ahmad (233201) Feras Q. Alali (16036197) Shahab Uddin (154400) |
| author2_role | author author author author author author author author author author author |
| author_facet | Shilpa Kuttikrishnan (3520079) Tariq Masoodi (8117702) Gulab Sher (12984698) Ajaz A. Bhat (158004) Kalyani Patil (2679424) Tamam El-Elimat (694398) Nicholas H. Oberlies (16036193) Cedric J. Pearce (16036196) Mohmmad Haris (12984704) Aamir Ahmad (233201) Feras Q. Alali (16036197) Shahab Uddin (154400) |
| author_role | author |
| dc.creator.none.fl_str_mv | Shilpa Kuttikrishnan (3520079) Tariq Masoodi (8117702) Gulab Sher (12984698) Ajaz A. Bhat (158004) Kalyani Patil (2679424) Tamam El-Elimat (694398) Nicholas H. Oberlies (16036193) Cedric J. Pearce (16036196) Mohmmad Haris (12984704) Aamir Ahmad (233201) Feras Q. Alali (16036197) Shahab Uddin (154400) |
| dc.date.none.fl_str_mv | 2022-07-01T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3389/fonc.2022.929996 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Bioinformatics_Analysis_Reveals_FOXM1_BUB1B_Signaling_Pathway_as_a_Key_Target_of_Neosetophomone_B_in_Human_Leukemic_Cells_A_Gene_Network-Based_Microarray_Analysis/23306132 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Cardiovascular medicine and haematology Oncology and carcinogenesis fungal metabolites Neosetophomone B FOXM1 BUB1B apoptosis leukemia cell-cycle checkpoints TCGA |
| dc.title.none.fl_str_mv | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>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 <em>BUB1B</em> 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 <em>BUB1B</em> compared to normal in most cancers and overexpression was associated with poor prognosis. <em>BUB1B</em> also showed a highly significant positive correlation with <em>FOXM1</em> in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an <em>in vitro</em> 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 <em>via</em> 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. </p> <h2>Other Information</h2> <p>Published in: Frointiers in Oncolgy<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br> See article on publisher's website: <a href="http://dx.doi.org/10.3389/fonc.2022.929996" target="_blank">http://dx.doi.org/10.3389/fonc.2022.929996 </a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_f980e61490ad01a97c28547bf3588685 |
| identifier_str_mv | 10.3389/fonc.2022.929996 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/23306132 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray AnalysisShilpa Kuttikrishnan (3520079)Tariq Masoodi (8117702)Gulab Sher (12984698)Ajaz A. Bhat (158004)Kalyani Patil (2679424)Tamam El-Elimat (694398)Nicholas H. Oberlies (16036193)Cedric J. Pearce (16036196)Mohmmad Haris (12984704)Aamir Ahmad (233201)Feras Q. Alali (16036197)Shahab Uddin (154400)Biomedical and clinical sciencesCardiovascular medicine and haematologyOncology and carcinogenesisfungal metabolitesNeosetophomone BFOXM1BUB1Bapoptosisleukemiacell-cycle checkpointsTCGA<p>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 <em>BUB1B</em> 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 <em>BUB1B</em> compared to normal in most cancers and overexpression was associated with poor prognosis. <em>BUB1B</em> also showed a highly significant positive correlation with <em>FOXM1</em> in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an <em>in vitro</em> 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 <em>via</em> 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. </p> <h2>Other Information</h2> <p>Published in: Frointiers in Oncolgy<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br> See article on publisher's website: <a href="http://dx.doi.org/10.3389/fonc.2022.929996" target="_blank">http://dx.doi.org/10.3389/fonc.2022.929996 </a></p>2022-07-01T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3389/fonc.2022.929996https://figshare.com/articles/journal_contribution/Bioinformatics_Analysis_Reveals_FOXM1_BUB1B_Signaling_Pathway_as_a_Key_Target_of_Neosetophomone_B_in_Human_Leukemic_Cells_A_Gene_Network-Based_Microarray_Analysis/23306132CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/233061322022-07-01T06:00:00Z |
| spellingShingle | Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis Shilpa Kuttikrishnan (3520079) Biomedical and clinical sciences Cardiovascular medicine and haematology Oncology and carcinogenesis fungal metabolites Neosetophomone B FOXM1 BUB1B apoptosis leukemia cell-cycle checkpoints TCGA |
| status_str | publishedVersion |
| 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 | Biomedical and clinical sciences Cardiovascular medicine and haematology Oncology and carcinogenesis fungal metabolites Neosetophomone B FOXM1 BUB1B apoptosis leukemia cell-cycle checkpoints TCGA |