title: Targeting of mutant p53-induced FoxM1 with thiostrepton induces cytotoxicity and enhances carboplatin sensitivity in cancer cells.
abstract: FoxM1 is an oncogenic Forkhead transcription factor that is overexpressed in ovarian cancer. However, the mechanisms by which FoxM1 is deregulated in ovarian cancer and the extent to which FoxM1 can be targeted in ovarian cancer have not been reported previously. In this study, we showed that MDM2 inhibitor Nutlin-3 upregulated p53 protein and downregulated FoxM1 expression in several cancer cell lines with wild type TP53 but not in cell lines with mutant TP53. FoxM1 downregulation was partially blocked by cycloheximide or actinomycin D, and pulse-chase studies indicate Nutlin-3 enhances FoxM1 mRNA decay. Knockdown of p53 using shRNAs abrogated the FoxM1 downregulation by Nutlin-3, indicating a p53-dependent mechanism. FoxM1 inhibitor, thiostrepton, induces apoptosis in cancer cell lines and enhances sensitivity to cisplatin in these cells. Thiostrepton downregulates FoxM1 expression in several cancer cell lines and enhances sensitivity to carboplatin in vivo. Finally, FoxM1 expression is elevated in nearly all (48/49) ovarian tumors, indicating that thiostrepton target gene is highly expressed in ovarian cancer. In summary, the present study provides novel evidence that both amorphic and neomorphic mutations in TP53 contribute to FoxM1 overexpression and that FoxM1 may be targeted for therapeutic benefits in cancers.
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
authors.forename: Lihua
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
authors.forename: Kay
authors.initials: K
authors.lastname: Minn
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
authors.forename: Rashna
authors.initials: R
authors.lastname: Madan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, U.S.A.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D013883:Thiostrepton / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D016190:Carboplatin; D013883:Thiostrepton