INBIOSUR   25013
INSTITUTO DE CIENCIAS BIOLOGICAS Y BIOMEDICAS DEL SUR
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
1ALFA,25(OH)2D3 AND TX527 REGULATE A20 AND BCATENIN IN ENDHOTELIAL CELLS TRANSFORMED BY KAPOSI SARCOMA-ASSOCIATED HERPES VIRUS G PROTEIN COUPLED RECEPTOR
Autor/es:
CINTHYA TAPIA; ALEJANDRA SUARES; VERÓNICA GONZALEZ PARDO
Lugar:
Orlando (Florida)
Reunión:
Congreso; Vitamin D Workshop 2017; 2017
Resumen:
The Kaposi?s Sarcoma-associated Herpes virus G Protein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi?s sarcoma. We have previously demonstrated that 1α,25(OH)2D3 or TX 527, similar to the proteasome inhibitor bortezomib, inhibit NF-B pathway and induce apoptosis in endothelial cells that express vGPCR. In this work, we studied the role of A20 and β-catenin regulation by VDR agonists, 1α,25(OH)2D3 and TX 527, in vGPCR cells. The deubiquitinating enzyme A20 is essential for maintaining immune homeostasis being a negative key regulator of inflammatory, antiviral and apoptotic signaling pathways. β-catenin, a multifunctional protein, is required for cell-cell adhesion and for regulation of gene expression in response to Wnt. Aberrant activation of this pathway provokes the accumulation of nuclear β-catenin and the induction of cell proliferation, which is critical for the initiation and progression in most type of cancers. Subcellular fractionation studies showed β Catenin presence in the nucleus during 48h treatments with 1α,25(OH)2D3 (10nM), which suggests β Catenin nuclear non-transcriptional accumulation due to the interaction with VDR receptor. Western blot analysis of time (3-48 h) and dose response (0.1-100 nM) showed that 1α,25(OH)2D3 or TX 527 (10 nM) decrease A20 and increase β-catenin protein expression. We found that both, A20 and β-catenin regulation by 1α,25(OH)2D3 or TX 527 treatment is suppressed when VDR expression was knockdown by shRNA against VDR. Moreover, A20 mRNA expression is also regulated by both compounds. In addition, Bortezomib (0.25-1 nM), similarly to VDR agonists, also decreases A20 and increases β-catenin protein levels in a dose-dependent manner. Taken together, all these events contribute to the anti-tumoral effect of 1α,25(OH)2D3 and TX 527 promoting NF-B inhibition through A20 regulation as part of the anti-proliferative mechanism of action.