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Methylseleninic acid inhibits microvascular endothelial G1 cell cycle progression and decreases tumor microvessel
Zhe Wang1, Hongbo Hu, Guangxun Li
1The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
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.
Insights
Methylseleninic acid (MSeA) halts microvascular endothelial cell cycle progression, inhibiting tumor growth and angiogenesis. This selenium compound targets cell cycle regulators, offering potential cancer chemoprevention strategies.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Selenium compounds, like methylseleninic acid (MSeA), exhibit cancer chemopreventive effects.
- Previous studies indicated MSeA induces G1 cell cycle arrest in macrovascular endothelial cells.
- The antiangiogenic activity of selenium is a potential mechanism for cancer chemoprevention.
Purpose of the Study:
- To confirm MSeA-induced G1 arrest in microvascular endothelial cells.
- To identify the molecular mediators and targets involved in MSeA's effects.
- To evaluate MSeA's efficacy in inhibiting tumor growth and angiogenesis in vivo.
Main Methods:
- Flow cytometry analyzed MSeA's effect on cell cycle progression in telomerase-immortalized microvascular endothelial (TIME) cells.
- Western blotting and mRNA analysis assessed the expression and activity of cell cycle regulatory proteins (p21/CIP1, p27/KIP1, p16/INK4a).
- In vivo studies utilized DU145 prostate cancer xenografts in nude mice treated with MSeA to assess tumor growth and microvessel density.
Main Results:
- MSeA induced a dose-dependent G1 arrest in TIME cells, delaying progression from G1 to S phase.
- MSeA modulated the expression and stability of cell cycle inhibitors (p21/CIP1, p27/KIP1, p16/INK4a), suppressed CDK activities, and inhibited Rb phosphorylation.
- In vivo, MSeA treatment significantly inhibited prostate tumor growth and reduced tumor microvessel density in a dose-dependent manner.
Conclusions:
- Methylseleninic acid effectively induces G1 arrest in microvascular endothelial cells by modulating key cell cycle regulators.
- MSeA demonstrates anti-tumor and anti-angiogenic properties, inhibiting endothelial cell proliferation and tumor vascularization.
- These findings support MSeA's potential as a chemopreventive agent targeting angiogenesis in cancer therapy.
