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Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic

Shilpa Kuttikrishnan1,2, Tariq Masoodi3, Gulab Sher1

  • 1Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

Frontiers in Oncology
|July 18, 2022
PubMed

Insights

Neosetophomone-B (NSP-B) suppresses Forkhead box protein M1 (FOXM1) and Budding uninhibited by benzimidazoles 1 (BUB1B) in leukemia cells. This highlights the FOXM1/BUB1B pathway as a potential therapeutic target for treating leukemia.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Abnormal expression of Forkhead box protein M1 (FOXM1) and Budding uninhibited by benzimidazoles 1 (BUB1B) is implicated in cancer development, including chronic myelogenous leukemia (CML).
  • The molecular mechanisms of the FOXM1/BUB1B regulatory network and the role of Neosetophomone-B (NSP-B) in leukemia are not well understood.
  • NSP-B, a fungal metabolite, shows anticancer potential in leukemia cell lines, but its mechanism of action requires elucidation.

Purpose of the Study:

  • To investigate the role of NSP-B in modulating the FOXM1/BUB1B signaling pathway in leukemic cells.
  • To elucidate the molecular mechanisms by which NSP-B induces apoptosis in leukemia.
  • To explore the therapeutic potential of targeting the FOXM1/BUB1B pathway in leukemia.

Main Methods:

  • Gene expression profiling of NSP-B-treated and untreated leukemic cells to identify differentially expressed genes.
  • TCGA data analysis to assess BUB1B and FOXM1 expression and correlation in various cancers.
  • In vitro validation using human leukemic cell lines (K562 and U937) to evaluate NSP-B's effects on FOXM1, BUB1B, and downstream targets.
  • siRNA-mediated suppression of FOXM1 and combination treatments with NSP-B and thiostrepton.

Main Results:

  • BUB1B was significantly downregulated in NSP-B-treated leukemic cells and its overexpression correlates with poor prognosis in various cancers.
  • BUB1B expression positively correlated with FOXM1 expression across TCGA cancer types.
  • NSP-B treatment suppressed FOXM1 and BUB1B expression in a dose-dependent manner in leukemic cells.
  • NSP-B downregulated FOXM1-regulated genes (Aurora kinase A, Aurora kinase B, CDK4, CDK6) and enhanced apoptosis.
  • Suppression of FOXM1 reduced BUB1B expression and promoted apoptosis; combination therapy with thiostrepton enhanced apoptosis via caspase-3 and caspase-8 activation.

Conclusions:

  • The FOXM1/BUB1B pathway plays a critical role in leukemia progression.
  • NSP-B effectively targets the FOXM1/BUB1B pathway, inducing apoptosis in leukemic cells.
  • Targeting the FOXM1/BUB1B pathway represents a promising therapeutic strategy for leukemia treatment.
Keywords:
BUB1BFOXM1Neosetophomone BTCGAapoptosiscell-cycle checkpointsfungal metabolitesleukemia

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