title: Retinoblastoma gene-independent G1 phase arrest by flavone, phosphatidylinositol 3-kinase inhibitor, and histone deacetylase inhibitor.
abstract: In most human malignant tumors, retinoblastoma tumor-suppressor gene (RB) product is inactivated by phosphorylation. Therefore, cancer preventive agents or molecular-targeting agents can inhibit the tumor growth at G(1)  phase through RB reactivation. However, little is known about the effectiveness of RB reactivating agents against malignancies with mutated RB. We report here that chemopreventive agent flavone, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, and histone deacetylase (HDAC) inhibitor trichostatin A (TSA) also induce G(1)  phase arrest in malignant tumor cells with mutated RB. In human prostate cancer DU145 cells with mutated RB, flavone increased cyclin-dependent kinase (CDK) inhibitors p21 and p27, and reduced cdk4 and cdk6, resulting in decrement of phosphorylated RB family proteins p130 and p107. LY294002 also dephosphorylated p107 and p130 proteins, whereas TSA dephosphorylated p130, but not p107. Furthermore, flavone induced G(1)  phase arrest in both mouse embryo fibroblast (MEF) wild-type and MEF RB(-/-)  cells, but did not do so in RB, p107, and p130 triple-knockout MEF cells. These results suggested that p130 and p107 contributed to G(1)  phase arrest by flavone in RB-mutated cells. However, flavone induced tumor suppressor microRNA miR-34a with reduction of E2F1 and E2F3, known to be downregulated by miR-34a, raising the possibility that miR-34a might partially contribute to G(1)  arrest by flavone. These results raise the possibility that RB reactivating chemopreventive agents or molecular targeting agents might also be effective against a variety of malignant tumor cells with mutant RB.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tomosugi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yasuda
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tanaka
authors.forename: Hein
authors.initials: H
authors.lastname: te Riele
authors.forename: Haruna
authors.initials: H
authors.lastname: Ikawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Koyama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D002867:Chromones / Q000494:pharmacology*; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000378:metabolism
chemical_list: C493841:BCAR1 protein, human; D002867:Chromones; D050719:Crk-Associated Substrate Protein; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C493844:RBL1 protein, human; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C012589:trichostatin A; D058539:Phosphatidylinositol 3-Kinase; D006655:Histone Deacetylases