1,25(OH)2vitamin D3 inhibits cell proliferation by promoting cell cycle arrest without inducing apoptosis and modifies cell morphology of mesenchymal multipotent cells.
The vitamin D receptor (VDR) and its ligand 1,25D play an important role in regulating cell growth and cell fate. We examined the effect of 1,25D on cell morphology, cell proliferation, cell cycle progression and apoptosis on mesenchymal multipotent cells. Multipotent cells were treated with and without 1,25D in a time- and dose-dependent manner. Changes in cell morphology were evaluated by a green fluorescence fluorocrome. Cell proliferation was determined by the Formazan assay and PCNA antigen expression. The expression of genes related to the cell cycle was analyzed by DNA microarrays, RT(2)PCR arrays and western blots. Apoptosis was evaluated by TUNEL assay, and the expression of pro- and anti-apoptotic related genes by RT(2)PCR arrays and western blots. 1,25D inhibited cell proliferation, induced cell cycle arrest, and promoted accumulation of cells in G0/G1 phase without inducing apoptosis. An increase in cell size was associated with a decrease in the GTPase Rho and the atypical Rho family GTPase Rhou/Wrch-1 expression without inducing Wnt-1 expression. Survivin expression was also increased and may represent a novel 1,25D-mediated pathway regulating tissue injury and fibrosis. The data provide a mechanistic explanation for the anti-proliferative and anti-apoptotic properties of 1,25D in mesenchymal multipotent cells.
Artaza
Jorge N
JN
Department of Internal Medicine, Charles Drew University of Medicine & Science, Los Angeles, CA 90059, USA. jorgeartaza@cdrewu.edu
Sirad
Fara
F
Ferrini
Monica G
MG
Norris
Keith C
KC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002117:Calcitriol / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D018816:Genes, cdc / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D020558:GTP Phosphohydrolases; D020742:rhoA GTP-Binding Protein; D002117:Calcitriol