Vitamin D Research Today is a free monthly online journal that collates and summarizes the latest research about Vitamin D, including details on sources, melanin, benefits, deficiency, supplements, calcium absorption. | ||||||||
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1alpha,25-Dihydroxyvitamin D(3) antiproliferative actions involve vitamin D receptor-mediated activation of MAPK pathways and AP-1/p21(waf1) upregulation in human osteosarcoma.Wu W, Zhang X, Zanello LP Department of Biochemistry, University of California, 5436 Boyce Hall, Riverside, CA 92521, USA. The molecular mechanisms underlying antiproliferative actions of the steroid 1alpha,25-dihydroxy vitamin D(3) (1,25D) in human osteosarcoma cells are known only partially. To better understand the signaling involved in 1,25D anti-tumorigenic properties in bone, we stably silenced vitamin D receptor (VDR) expression in the human osteosarcoma SaOS-2 cell line. We found that 1,25D treatment reduced cell proliferation by approximately 25% after 3 days only in SaOS-2 cells expressing native levels of VDR protein, and involved activation of MAPK/AP-1/p21(waf1) pathways. Both sustained (3 days) and transient (15min) 1,25D treatment activated JNK and ERK1/2 MAPK signaling in a nongenomic VDR-dependent manner. However, only sustained exposure to hormone led to upregulation of p21 and subsequent genomic control of the cell cycle. Specific blockade of MEK1/MEK2 cascade upstream from ERK1/2 abrogated 1,25D activation of AP-1 and p21, and subsequent antiproliferative effects, even in the presence of a nuclear VDR. We conclude that 1,25D-induced inhibition of human osteosarcoma cell proliferation occurs via sustained activation of JNK and MEK1/MEK2 pathways downstream of nongenomic VDR signaling that leads to upregulation of a c-Jun/c-Fos (AP-1) complex, which in turn modulates p21(waf1) gene expression. Our results demonstrate a cross-talk between 1,25D/VDR nongenomic and genomic signaling at the level of MAP kinase activation that leads to reduction of cell proliferation in human osteosarcoma cells. Published 30 July 2007 in Cancer Lett, 254(1): 75-86.
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