Activation of rapid signaling pathways does not contribute to 1α,25‐dihydroxyvitamin D₃‐induced growth inhibition of mouse prostate epithelial progenitor cells

Abstract

The active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) inhibits the growth of prostate epithelial cells, however the underlying mechanisms have not been clearly delineated. In the current study, the impact of 1,25(OH)2D on the rapid activation of extracellular-regulated kinase (ERK) 1/2 and protein kinase C α (PKCα), and the role of these pathways in growth inhibition was examined in immortalized mouse prostate epithelial cells, MPEC3, that exhibit stem/progenitor cell characteristics. 1,25(OH)2D treatment suppressed the growth of MPEC3 in a dose and time dependent manner (e.g., 21% reduction at three days with 100 nM 1,25(OH)2D treatment). However, ERK1/2 activity was not altered by 100 nM 1,25(OH)2D treatment for time points from 1 min to 1 h in either serum-containing or serum-free medium. Similarly, PKCα activation (translocation onto the plasma membrane) was not regulated by short-term treatment of 100 nM 1,25(OH)2D. In conclusion, 1,25(OH)2D did not mediate rapid activation of ERK1/2 or PKCα in MPEC3 and therefore the growth inhibitory effect of 1,25(OH)2D is independent of rapid activation of these signaling pathways in this cell type.

Interleukin-1α Mediates the Antiproliferative Effects of 1,25-Dihydroxyvitamin D3 in Prostate Progenitor/Stem Cells

“…A clonal population, WFU3 clone 3 (WFU3 cl.3), exhibited multilineage differentiation and self-renewal in vivo , and they expressed known progenitor cell markers Sca1 and CD49f as well as basal cell markers p63 and cytokeratins 5 and 14. A previous study verified 1,25(OH) 2 D 3 -mediated growth inhibition of the parental cell line WFU3, but the mechanism is unknown (31). In this study, we used the characterized WFU3 cl.3 cells, hereafter called prostate progenitor/stem cells (PrP/SC), to study the phenotypic and genotypic effects of 1,25(OH) 2 D 3 .…”

Vitamin D: An innate antiviral agent suppressing hepatitis C virus in human hepatocytes

“…However, there is substantial evidence for additional extrarenal sites of production of calcitriol, which primarily serves as an autocrine/paracrine factor with cell‐specific functions 9. 1α‐Hydroxylase has been reported in many cells and tissues including the skin, prostate, brain, breast, colon, lung, pancreatic islets, lymph nodes, monocytes, parathyroid, placenta, colonic epithelial cells, and in adipose tissue 9‐12. However, to the best of our knowledge, no previous reports have shown either the expression of 1α‐hydroxylase in hepatocytes or the synthesis of calcitriol in these cells.…”

“…25(OH)D, the major circulating form of vitamin D, is transported to the kidney, where it undergoes a second hydroxylation into the active form of the hormone, 1α,25‐dihydroxyvitamin D [1α,25(OH)2D or calcitriol] by 25‐hydroxyvitamin‐D 1α‐hydroxylase (1α‐hydroxylase) 7, 8. The systemic levels of calcitriol are mainly determined by the renal enzyme, although the local production of calcitriol from 25(OH)D has now been demonstrated in many extrarenal cells and tissues 9‐12. Most biological effects of calcitriol are mediated through the vitamin D receptor (VDR), a member of the nuclear receptor superfamily of ligand‐activated transcription factors 6.…”

Molecular assessment of vitamin D receptor polymorphism as a valid predictor to the response of interferon/ribavirin‐based therapy in Egyptian patients with chronic hepatitis C

“…A controversy has arisen as to why HCV replication inhibition has occurred. From one point of view, the reason for this inhibition is the role of calcitriol, which is produced in several tissues including the immune cells, as it plays a crucial role in manipulating cell functions by either autocrine or paracrine mechanisms . Furthermore, hepatocytes in an in vitro model were shown to express 1α‐hydroxylase, leading to the production of calcitriol .…”

“…From one point of view, the reason for this inhibition is the role of calcitriol, which is produced in several tissues including the immune cells, as it plays a crucial role in manipulating cell functions by either autocrine or paracrine mechanisms. 16 Furthermore, hepatocytes in an in vitro model were shown to express 1α-hydroxylase, leading to the production of calcitriol. 15 A second study investigating the mechanism of vitamin D was performed by Matsumura et al 17 who found that 25-(OH) D, and not 1,25(OH) 2 D, can suppress viral replication by reducing the viral assembly step.…”