title: Methylseleninic acid inhibits microvascular endothelial G1 cell cycle progression and decreases tumor microvessel density.
abstract: Our previous work has shown that the cancer chemopreventive effect of selenium may in part be mediated by its antiangiogenic activities and that methylseleninic acid (MSeA) can induce G1 arrest of human umbilical vein endothelial (macrovascular) cells. The objectives of the current study are to verify MSeA-induced G1 arrest effect in microvascular endothelial cells and to elucidate the molecular mediators and targets involved. Flow cytometric analysis after MSeA exposure (2-10 microM) of telomerase-immortalized microvascular endothelial (TIME) cells for 24 hr showed aconcentration-dependent increase of G1-arrested cells. MSeA (3 microM) treatment delayed the mitogen-stimulated progression of TIME cells from G1 to S phase. These effects of MSeA were accompanied by an early transient (6 hr) upregulation of P21/CIP1 and P27/KIP1 and a delayed modest increase of P16/INK4a (12 hr). MSeA increased P27/KIP1 mRNA transcript level and slowed the turnover of P21/CIP1 protein. MSeA-treated cells contained elevated levels of bound P16/INK4a within the CDK4/6/cyclin D1 complexes as well as bound P21/CIP1 and P27/KIP1 within the CDK2/cyclin E complex and decreased their kinase activities. MSeA suppressed the mitogen/CDK-driven phosphorylative inactivation of retinoblastoma (Rb) protein, diminishing E2F1 release from Rb. In vivo, daily oral MSeA treatment of nude mice bearing subcutaneously inoculated human prostate cancer DU145 xenografts inhibited tumor growth in a dose-dependent manner. The microvessel density of the tumors in the high MSeA group was decreased by more than half from the control. An inhibition of mitogen-stimulated proliferation of endothelial cells by MSeA may therefore contribute to the inhibition of tumor angiogenesis.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.forename: Guangxun
authors.initials: G
authors.lastname: Li
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lü
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000098:blood supply*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D016566:Organoselenium Compounds; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; C008493:methylselenic acid; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D001973:Bromodeoxyuridine