1α,25‐dihydroxyvitamin D₃‐mediated stimulation of steroid sulphatase activity in myeloid leukaemic cell lines requires VDR_nuc‐mediated activation of the RAS/RAF/ERK‐MAP kinase signalling pathway

Abstract

1Alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) stimulates the activity of steroid sulphatase (STS) in myeloid cells [Hughes et al., 2001, 2005]. This was attenuated by inhibitors of phospholipase D (PLD) (n-butanol, 2,3-diphosphoglyceric acid, C(2)-ceramide) and phosphatidate phosphohydrolase (PAP) (propranolol and chlorpromazine), but was unaffected by inhibitors of phospholipase C. The 1alpha,25(OH)(2)D(3)-induced STS activity was also attenuated by inhibitors of protein kinase Calpha and protein kinase Cdelta (Go 6976, HBDDE and rottlerin), but not by an inhibitor of protein kinase Cbeta (LY379196). Additionally, 1alpha,25(OH)(2)D(3)-induced STS activity was attenuated by inhibitors of RAS (manumycin A), RAF (GW5074), MEK (PD098059 and U1026) and JNK (SP600125), but not p38 (PD169316). 1alpha,25(OH)(2)D(3) produced a rapid and long lasting stimulation of the ERK-MAP kinase signalling cascade in HL60 myeloid leukaemic cells. This 'non-genomic' effect of 1alpha,25(OH)(2)D(3) blocked by pharmacological antagonists of nuclear vitamin D receptors (VDR(nuc)) and does not appear to require hetero-dimerisation with the retinoid-X receptor (RXR). Inhibitors of the Src tyrosine kinase (PP1), RAS (manumycin A), RAS-RAF interactions (sulindac sulphide and RAS inhibitory peptide), RAF (GW5074 or chloroquine), and protein kinase Calpha (HBDDE) abrogated the 1alpha,25(OH)(2)D(3)-stimulated increase in ERK-MAP kinase activity. Taken together, these results show that 1alpha,25(OH)(2)D(3)/VDR(nuc) activation of the RAS/RAF/ERK-MAP kinase signalling pathway plays an important role in augmenting STS activity in human myeloid leukaemic cell lines.

Beta-1 integrins mediate substrate dependent effects of 1α,25(OH)2D3 on osteoblasts

“…Integrin signaling can influence gene expression via ERK activation (5786) and we have shown that blocking activation of ERK1/2 with PD98059 affects osteoblast response to surface microstructure [19]. ERK1/2 also mediates some of the effects of 1α,25(OH) 2 D 3 signaling via ERp60 [20] and others have shown that ERK1/2 participates in responses to 1α, 25(OH) 2 D 3 via the VDR [21]. Thus, by modifying osteoblast differentiation via changes in substrate topography, resulting changes in ERK1/2 may modify the actions of 1α,25 (OH) 2 D 3 through multiple mechanistic pathways.…”

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

“…The activation of Ras/MAPK or the presence of oncogenic Ras was shown to enhance TGF-hinduced epithelial-mesenchymal transition (33,34). More importantly, it has been shown that 1a,25(OH) 2 D 3 regulates the MAPK pathway by activating Ras/RAF-1 signaling in muscle cells and in myeloid leukemic cells (17,18). We showed in this report that the vitamin D 3 analogue Ro3582 increased phosphorylation of Smad1/5 and inhibited cell proliferation in MCF10AT1 cells transfected with Ha-ras, but not in the parent MCF10A cells that lack Ras (Fig.…”

“…The effects of 1a,25(OH) 2 D 3 and its analogues are mainly mediated through the vitamin D receptor (VDR) or through the membrane-associated signaling pathway (1,15). Membrane-associated responses to 1a,25(OH) 2 D 3 [nongenomic, rapid response to 1a,25(OH) 2 D 3 ], where the mechanism is still unclear, is now considered an essential type of action involved in calcium/phosphate transport, activation of protein kinase C (PKC), and/or the mitogen-activated protein kinase (MAPK) cascade (15)(16)(17)(18).…”

“…The PKC family is a group of serine/threonine kinases known to regulate cell growth, apoptosis, differentiation, cell migration, and carcinogenesis in different types of cells and models (21,22). Boyan et al (19,20) suggest that a caveolar environment may play an important role in mediating the PKC activation by 1a,25(OH) 2 (17,18).…”

Dual role of hematopoietic progenitor kinase 1 (HPK1) as a positive regulator of 1α,25-dihydroxyvitamin D-induced differentiation and cell cycle arrest of AML cells and as a mediator of vitamin D resistance

“…13 MAPK signaling, along with PI3K/Akt/mTOR, Src kinase, PKC and JAK-STATs are among the major networks that respond to various environmental stimuli and participate in the actions of vitamin D to regulate cell survival, proliferation, differentiation and apoptosis. 7,[14][15][16][17][18][19][20] Several components of MAPK pathways, such as MEKs and ERKs as well as the β-catenin pathway, interact with the classical 1,25D-mediated pathway through direct binding of VDR and then cross-activation of transcription of its target genes. 21,22 Other genes also play key roles in cell differentiation; for instance, the KSR-MAPK-C/EBP pathway is critical to the VDD-induced monocytic differentiation in HL60 cells.…”