Methylseleninic acid inhibits microvascular endothelial G1 cell cycle progression and decreases tumor microvessel density.

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.

Wang Z ，Hu H ，Li G ，Lee HJ ，Jiang C ，Kim SH ，Lü J ... -  《-》

Persistent p21Cip1 induction mediates G(1) cell cycle arrest by methylseleninic acid in DU145 prostate cancer cells.

Wang Z ，Lee HJ ，Chai Y ，Hu H ，Wang L ，Zhang Y ，Jiang C ，Lü J ... -  《-》

Depletion of SUMO ligase hMMS21 impairs G1 to S transition in MCF-7 breast cancer cells.

hMMS21 is a human SUMO ligase required for DNA damage repair and mitotic progression in HeLa cervical cancer cells. Owing to the diversity of cancer, we further investigated the effect of hMMS21-depletion on MCF-7 breast cancer cells. hMMS21-depletion was achieved by RNA interference. Cellular hMMS21 and E2F1 mRNA levels were estimated by RT-PCR and real-time PCR. Cell cycle profile was assessed by flow cytometry. Western blot and co-immunoprecipitation were used to determine the protein levels of various factors involved in G1-S transition and CDK2- or CDK4-associated p21 and p27. Kinase activity of cyclin E/CDK2 was measured in anti-cyclin E immunoprecipitate. hMMS21-depletion induced slower cell growth and G1-S transition. While it had no effect on cyclin D1 or phospho-Rb (S807/811) levels, hMMS21-depletion provoked lower E2F1 levels and cyclin E/CDK2 activity. The decreased cyclin E/CDK2 activity correlated with increased cellular p21(CIP1) levels and CDK2-p21 association. Moreover, ectopic expression of Flag-hMMS21 but not its ligase-inactive mutant rescued the decreased growth rates of hMMS21-depletd cells. Thus, depletion of hMMS21 seems to impair G1-S transition due to lowered E2F1 protein levels and cyclin E/CDK2 activity. The decreased cyclin E/CDK2 activity is probably attributable to its greater association with p21 as a result of increased p21 levels. In addition, hMMS21-mediated sumoylation appears to be involved. This study demonstrates that hMMS21 is required for G1-S transition in breast cancer cells and implies that manipulation of hMMS21-mediated sumoylation may alter the growth rates of breast cancer cells.

Ni HJ ，Chang YN ，Kao PH ，Chai SP ，Hsieh YH ，Wang DH ，Fong JC ... -  《-》

Sodium ascorbate inhibits growth via the induction of cell cycle arrest and apoptosis in human malignant melanoma A375.S2 cells.

Lin SY ，Lai WW ，Chou CC ，Kuo HM ，Li TM ，Chung JG ，Yang JH ... -  《MELANOMA RESEARCH》

Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells.

Jiang C ，Wang Z ，Ganther H ，Lü J ... -  《MOLECULAR CANCER THERAPEUTICS》