title: A Novel Function of Molecular Chaperone HSP70: SUPPRESSION OF ONCOGENIC FOXM1 AFTER PROTEOTOXIC STRESS.
abstract: The oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers, and it is a potential target for anticancer therapy. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Here we found that HSP90 inhibitor PF-4942847 and heat shock also suppress FOXM1. The common effector, which was induced after treatment with proteasome and HSP90 inhibitors or heat shock, was the molecular chaperone HSP70. We show that HSP70 binds to FOXM1 following proteotoxic stress and that HSP70 inhibits FOXM1 DNA-binding ability. Inhibition of FOXM1 transcriptional autoregulation by HSP70 leads to the suppression of FOXM1 protein expression. In addition, HSP70 suppression elevates FOXM1 expression, and simultaneous inhibition of FOXM1 and HSP70 increases the sensitivity of human cancer cells to anticancer drug-induced apoptosis. Overall, we determined the unique and novel mechanism of FOXM1 suppression by proteasome inhibitors.
authors.affiliation: From the Departments of Medicine and.
authors.forename: Marianna
authors.initials: M
authors.lastname: Halasi
authors.affiliation: Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Renáta
authors.initials: R
authors.lastname: Váraljai
authors.affiliation: Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60612.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Benevolenskaya
authors.affiliation: From the Departments of Medicine and Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60612 agartel@uic.edu.
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Gartel
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018840:HSP70 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D004247:DNA
keywords: 70-kD heat shock protein (Hsp70); FOXM1; anticancer drug; cell death; gene expression; protein-protein interaction