Thiostrepton inhibits growth and induces apoptosis by targeting FoxM1/SKP2/MTH1 axis in B-precursor acute lymphoblastic leukemia cells

Abstract

Forkhead box M1 (FoxM1) is a transcription factor that plays an important role in the etiology of many cancers, however, its role has not been elucidated in B-precursor acute lymphoblastic leukemia (B-pre-ALL). In the current study, we showed that the downregulation of FoxM1 by its inhibitor thiostrepton inhibited cell viability and induced caspase-dependent apoptosis in a panel of B-pre-ALL cell lines. Thiostrepton led downregulation of FoxM1 accompanied by decreased expression of Aurora kinase A, B, matrix metalloproteinases, and oncogene SKP2 as well as MTH1. Downregulation of the FoxM1/SKP2/MTH1 axis led to increase in the Bax/Bcl2 ratio and suppression of antiapoptotic proteins. Thiostrepton-mediated apoptosis was prevented by N-acetyl cysteine, a scavenger of reactive oxygen species. Co-treatment of B-pre-ALL with subtoxic doses of thiostrepton and bortezomib potentiated the proapoptotic action. Altogether, our results suggest that targeting FoxM1expression could be an attractive strategy for the treatment of B-pre-ALL.

Keywords:

• B-pre-ALL
• Bortezomib
• FoxM1
• MTH1: SKP2
• Thiostrepton

Acknowledgement

This work was supported by the grants funded by Medical Research center (MRC), Hamad Medical corporation, Doha, Qatar (MRC# 16354/16).

Author contributions

Author’s contribution: SK, performed experiment and help in experiment designing, data analysis and manuscript writing, KSP, AQK, performed data analysis and proof reading; AA help manuscript writing, editing, proofreading SU: Experiment design, data analysis and manuscript writing and proofreading

Disclosure statement

No potential conflict of interest was reported by the author(s).