The oncogenic
transcription factor FOXM1 is one of the key regulators of
tumorigenesis. We found that FOXM1 upregulates its own transcription and its protein stability depends on its interaction with the chaperone
nucleophosmin. We also determined that FOXM1 is negatively regulated by the
tumor suppressor p53. We identified the
thiazole antibiotics Siomycin A and
thiostrepton as inhibitors of transcriptional activity and FOXM1 expression via
proteasome inhibition. In addition, we found that all tested
proteasome inhibitors target FOXM1. We showed synergy between
thiostrepton and
bortezomib in different human
cancer cell lines and in vivo. We generated isogenic human
cancer cell lines of different origin with wild-type p53 or p53 knockdown and we demonstrated that
proteasome inhibitors induce p53-independent apoptosis in these cells. Using RNA-interference or
proteasome inhibitors to inhibit FOXM1 we found that suppression of FOXM1 sensitized human
cancer cells to apoptosis induced by
DNA-damaging agents or oxidative stress. We encapsulated
thiostrepton into
micelle-nanoparticles and after injection we detected accumulation of nanoparticles in
tumors and in the livers of treated mice. This treatment led to inhibition of human xenograft
tumor growth in nude mice. Our data indicate that targeting FOXM1 increases apoptosis and inhibits
tumor growth.