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Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis

Version 2 2024-01-28, 05:05
Version 1 2023-06-13, 09:58
journal contribution
revised on 2024-01-28, 05:03 and posted on 2024-01-28, 05:05 authored by Shilpa Kuttikrishnan, Tariq Masoodi, Gulab Sher, Ajaz A. Bhat, Kalyani Patil, Tamam El-Elimat, Nicholas H. Oberlies, Cedric J. Pearce, Mohmmad Haris, Aamir Ahmad, Feras Q. Alali, Shahab Uddin

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. 

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Published in: Frointiers in Oncolgy
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Open Access funding provided by the Qatar National Library.



  • English



Publication Year

  • 2022

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This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Medical Corporation
  • Academic Health System - HMC
  • Dermatology Institute - HMC
  • Interim Translational Research Institute - HMC
  • Qatar University
  • Laboratory Animal Research Center - QU
  • Qatar University Health - QU
  • College of Pharmacy - QU HEALTH
  • Sidra Medicine

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