Inhibition of MG-63 cell cycle progression by synthetic vitamin D3 analogs mediated by p27, Cdk2, cyclin E, and the retinoblastoma protein


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Abstract

Progression through eukaryotic cell division cycle is regulated by synergistic activities of both positive and negative regulatory factors. The active form of vitamin D3 (1α,25(OH)2D3, 1,25D) and a number of its synthetic analogs have been shown to arrest cells in the G1 phase of the cell cycle. In the present study, 1α,25(OH)2D3 and the analogs KH1060, EB1089, and CB1093 were used to study the mechanism of the cell cycle arrest and to compare the effectiveness of these compounds in human MG-63 osteosarcoma cells. The 20-epi analogs KH1060 and CB1093, as well as the 20-normal analog EB1089, were found to be more potent than 1α,25(OH)2D3 in inhibiting cell proliferation and arresting the MG-63 cells in the G1 phase. These analogs were more active than 1α,25(OH)2D3 in increasing the cyclin dependent kinase inhibitor p27 protein levels (approximately 2.3-2.5-fold compared to 1α,25(OH)2D3) by both increasing its formation and decreasing its degradation rate. The increased p27 formation was accompanied by stabilization of binding of nuclear proteins to the Sp1+NF-Y responsive promoter region of the p27 gene. The increase in p27 protein levels and the simultaneous decrease in cyclin E protein levels was accompanied by decreased Cdk2 kinase activity, retinoblastoma (Rb) protein hypophosphorylation and, finally, cell cycle arrest in the G1 phase. In summary, the analogs KH1060, EB1089, and CB1093 keep Rb protein in its growth-suppressing, hypophosphorylated form and prevent cell cycle progression through the restriction point. Therefore, these synthetic vitamin D3 analogs may be potential candidates for treating diseases, where cell cycle regulation is needed.

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