Targeting Forkhead Box M1 (FOXM1) in Human Cancer

Targeting Forkhead Box M1 (FOXM1) in Human Cancer Marianna Halasi Department of Biochemistry and Molecular Genetics University of Illinois at Chicago Chicago, Illinois (2012) Dissertation Chairperson: Pradip Raychaudhuri Forkhead Box M1 (FOXM1) is an oncogenic transcription factor of the Forkhead family with an important role in cell proliferation and cell cycle progression. However, in recent years it has become a significant factor in cancer development. To date published data support examining the potential of FOXM1 targeting. Our laboratory identified thiazole antibiotics as potent FOXM1 inhibitors. Investigation of the mechanism of action of these FOXM1 inhibitors revealed a novel positive autoregulation of FOXM1. We demonstrate that the thiopeptides exhibit proteasome inhibitory activity and that bona-fide proteasome inhibitors also inhibit FOXM1. We show that FOXM1/proteasome inhibitors efficiently downregulate the protein expression of FOXM1, induce cell death in cancer cells, and reduce tumor growth in xenograft models of human breast and pancreatic cancer. We also evaluated targeting FOXM1 in combination with DNA-damage and oxidative stress. We demonstrate that RNAi-mediated knockdown of FOXM1 sensitizes cancer cells to apoptosis induced by DNA-damaging agents and ROS inducers. Moreover, we show that combination of FOXM1/proteasome inhibitors and DNA-damaging agents or ROS inducers leads to potent apoptosis. We found that JNK activation and Bcl-2 downregulation after suppression of FOXM1 may be the underlying mechanism for the increased cell death following DNA-damage. In addition, we show evidence that FOXM1/proteasome inhibitors in combination with ROS inducers efficiently suppress the growth of breast tumor xenografts. Our findings provide compelling evidence that FOXM1 is a suitable target for single or combinatorial anticancer therapy.