The vitamin D receptor‐mediated activation of phosphatidylinositol 3‐kinase (PI3Kα) plays a role in the 1α,25‐dihydroxyvitamin D₃‐stimulated increase in steroid sulphatase activity in myeloid leukaemic cell lines

Abstract

In this article we show that 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) stimulates the activity of the class IA phosphatidylinositol 3-kinase PI3Kalpha and its downstream target Akt in HL60, U937 and THP-1 myeloid leukaemic cell lines. Furthermore, we show that the classical nuclear vitamin D receptor (VDR(nuc)) is involved in this activation of the PI3K/Akt signalling in these cell lines. We have previously shown that the activity of steroid sulphatase is stimulated in HL60, U937 and THP-1 myeloid leukaemic cell lines by 1alpha,25(OH)(2)D(3) (Hughes et al., [2001] Biochem J 355:361-371; Hughes et al., [2005] J Cell Biochem 94:1175-1189; Hughes and Brown [2006] J Cell Biochem 98:590-617). In this article we show that the 1alpha,25(OH)(2)D(3)-stimulated increase in signalling via the PI3K/Akt pathway plays a role in the increase in steroid sulphatase activity in the HL60 U937 and THP-1 cell lines. We used a variety of pharmacological and biochemical approaches to show that activation of PI3Kalpha mediates the 1alpha,25(OH)(2)D(3)-stimulated increase in steroid sulphatase activity in myeloid leukaemic cells. We also show that the PI3K/Akt dependent activation of NF-kappaB plays a role in the 1alpha,25(OH)(2)D(3)-stimulated increase in steroid sulphatase activity in myeloid leukaemic cells.

Circulating 25-Hydroxyvitamin D, IRS1 Variant rs2943641, and Insulin Resistance: Replication of a Gene–Nutrient Interaction in 4 Populations of Different Ancestries

“…The IRS1 variant rs2943641 C allele has been shown to disrupt the insulin signaling pathway by reducing IRS1 protein expression and its downstream phosphatidylinositol-3-OH kinase activity in a functional test (4). In contrast, 1,25(OH)D may stimulate the activity of phosphatidylinositol-3-OH kinase (30). Therefore, the beneficial effect of higher circulating 25(OH)D on the insulin signaling pathway and insulin sensitivity may be blocked by this diabetogenic risk allele, while individuals carrying the nonrisk TT genotype could still see benefit from high 25(OH)D status.…”

Inhibitors for the Vitamin D Receptor–Coregulator Interaction

“…In addition, the agonistic effects of ZK168281 increased with VDR H302A and H397A mutations (138). Finally, ZK168281 inhibited the phosphorylation of phosphoinositide mediated by phosphatidylinositol 3-kinase in the presence of 1,25-(OH) 2 D 3 (111). …”

“…(107) In addition, ZK159222 inhibited the phosphorylation of Raf-1(108, 109) and the expression of pRb and c/EBPβ in the presence of 1,25-(OH) 2 D 3 . (110) ZK159222 inhibited the phosphorylation of phosphoinositide and Akt-mediated by phosphatidylinositol 3-kinase in the presence of 1,25-(OH) 2 D 3 (111). Furthermore, ZK159222 inhibited the steroid sulphatase activity in the presence of 1,25-(OH) 2 D 3 in HL60 cells (112).…”

Induction of steroid sulfatase expression by tumor necrosis factor-α through phosphatidylinositol 3-kinase/Akt signaling pathway in PC-3 human prostate cancer cells

“…Because MG-132 is able to inhibit NF-κB activity by preventing the proteasomal degradation of IκBα, NF-κB signaling pathway may also play an important role in STS gene expression by TNF-α. Previous report indicated that 1α,25-dihydrovitamin D 3 stimulates steroid sulfatase activity through NF-κB pathway in myeloid leukemic cells such as HL-60 and THP-1 (Hughes et al, 2008). Because NF-κB signaling pathway may control STS gene expression by TNF-α as well as 1α,25-dihydrovitamin D 3 , it will be necessary to determine what mechanism is involved in this event.…”