FOXM1 is overexpressed in B-acute lymphoblastic leukemia (B-ALL) and its inhibition sensitizes B-ALL cells to chemotherapeutic drugs

Abstract

The Forkhead box protein M1 (FOXM1) is a transcription factor that plays a central role in the regulation of cell cycle, proliferation, DNA repair, and apoptosis. FOXM1 is overexpressed in many human tumors and its upregulation has been linked to high proliferation rates and poor prognosis. We therefore studied the role of FOXM1 in B-lymphoblastic leukemia (B-ALL) in order to understand whether FOXM1 could be a key target for leukemia therapy. RT-PCR and western blot analysis were carried out in a small cohort of pediatric B-ALL patients to evaluate FOXM1 levels. To assess its biological relevance, its expression was down-modulated by transient RNA interference in B-ALL cell lines (REH and NALM-6). Our results show that FOXM1 expression is higher in both B-ALL patients and cell lines when compared to PBMC or normal B-cells (CD19+) from healthy donors. Furthermore, blocking FOXM1 activity in two B-ALL cell lines, by either knockdown or treatment with the FOXM1 inhibitor thiostrepton, causes significant decrease in their cell proliferation. This decrease in cell proliferation was coupled with both an induction of the G2/M cell cycle arrest and with a reduction in the S phase population. Finally, we noted how thiostrepton synergises with chemotherapeutic agents commonly used in B-ALL therapy, thus increasing their efficiency. Therefore our results suggest that FOXM1 is highly expressed in both patients and B-ALL cell lines, and that targeting FOXM1 could be an attractive strategy for leukemia therapy and for overcoming drug resistance.

<p>FoxM1 is Upregulated in Osteosarcoma and Inhibition of FoxM1 Decreases Osteosarcoma Cell Proliferation, Migration, and Invasion</p>

“…18 In addition, FoxM1 promotes B-ALL cell proliferation and drug resistance through transcriptional activation of cyclin B1 and Aurora B, two critical regulators of the G2/M phase. 19 In alignment with these previous findings, our mechanistic studies showed that FoxM1 downregulation by thiostrepton or shRNA-mediated gene silencing caused G2/M-phase arrest in human MG-63 and HOS-MNNG OS cells. Previous studies have reported that FoxM1 inhibition by thiostrepton induces cell death through caspase-dependent intrinsic and extrinsic apoptotic pathways in breast cancer cells 20 and that FoxM1 knockdown in hypopharyngeal squamous cell carcinoma promotes apoptotic cell death.…”

Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma

“…Targeting the interactions and pathways described above – perhaps in conjunction with targeting FOXM1 directly using established [ 43 ] or emerging [ 44 ] small-drug inhibitors – may afford the re-sensitization of relapsed FOXM1 High myeloma to Bz and other drugs that were effective at earlier stages of myeloma therapy. A variety of molecularly targeted chemo-sensitization approaches of this sort are pursued in myeloma [ 45 ] – all attempting to build on findings in B-ALL that demonstrate that drug resistance in malignant B lymphocytes may be overcome by suppression of FOXM1 [ 46 ].…”

Activity of cyclin B1 in HL-60 cells treated with etoposide

“…Silencing the FOXM1 expression resulted in depletion of cell cycle regulators such as cyclin B1, Aurora, Survivin and Cdc25b. Moreover, inhibition of FOXM1 by thiostrepton sensitized B-ALL cells for anticancer drugs (Consolaro et al, 2015). Over expression of cyclin B1 were also observed in human non-small cell lung cancer (Salmón et al, 2009;Yoshida et al, 2004).…”