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MECHANISM OF 1,25(OH) 2 ‐VITAMIN D 3 ‐INDUCED GROWTH INHIBITION OF TRANSFORMED ENDOTHELIAL CELLS
Author(s) -
Pardo Veronica Gonzalez,
Boland Ricardo,
Boland Ana Russo
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.560.2
We have previously demonstrated that 1,25(OH) 2 ‐Vitamin D 3 (1,25(OH) 2 D 3 ) has antiproliferative effects on the growth of endothelial cells transformed by the viral G protein‐coupled receptor associated to Kaposi sarcoma (KSHV‐GPCR). In this work, we have investigated whether 1,25(OH) 2 D 3 exerts its growth inhibitory effects by interfering with the NFkB pathway which is activated by vGPCR and serum in endothelial cells (SVEC). Time (4–48 h) and dose (0.1–100 nM) response studies showed that the hormone decreases NFkB and increases IkBá protein levels in SVEC and SVEC‐vGPCR cells, the highest response taking place at 16 h and 10 nM 1,25(OH) 2 D 3 . Moreover, inhibition of NFkB translocation to the nucleus was observed and occurred by a mechanism independent of NFkB association with vitamin D 3 receptor (VDR). IkBá protein synthesis was decreased in presence of cycloheximide, demonstrating that de novo IkBá synthesis is induced by 1,25(OH) 2 D 3 . The role of Akt and MAPK pathways on hormone modulation of NFkB was investigated. The results indicated that inhibition of Akt by LY 249002 mimics 1,25(OH) 2 D 3 induction of IkBá protein levels without changes on NFkB. Inhibition of MAPKs did not modify protein levels of NFkB or IkBá. Altogether, these results suggest that the antiproliferative effects of 1,25(OH) 2 D 3 on endothelial cells and SVEC transformed by vGPCR occurred by down‐regulation of the NFkB pathway.