Vitamin D Receptor Signaling and Cancer

Abstract

The primary biological action of the secosteroid hormone vitamin D (1,25(OH) 2 D 3 ) is to bind to the vitamin D receptor (NR1I1/VDR) and to regulate serum calcium levels. As a downstream consequence, the actions of the receptor control bone formation and maintenance. The first clinical manifestation of insufficient VDR endocrine signaling, rickets, was discovered by Daniel Whistler in the Netherlands in the 17th century; 300 years later, the VDR gene was cloned by Bert O'Malley and coworkers. 1 Between these dates, research into vitamin D was at the forefront of areas of public health, chemistry and biochemistry including the light catalyzed synthesis of vitamin D 3 by Adolf Windaus. For this work, he received the Nobel Prize in Chemistry (1928). Work in the 1960s and 1970s led to analyses of vitamin D endocrine metabolism and led to remarkable strides describing biochemical synthesis of 1,25(OH) 2 D 3 and the diverse biology in which VDR participates.The precursor of 1,25(OH) 2 D 3 , cholecalciferol or vitamin D 3 , is produced in the skin and converted in the liver to 25-hydroxyvitamin D 3 , (25(OH)D 3 ); circulating levels of 25(OH)D 3 serve as a useful index of vitamin D total body stores. A further hydroxylation occurs in the principally in the kidney at the carbon 1 position by 25-hydroxyvitamin D-1α-hydroxylase (encoded by CYP27B1) to produce the biologically active hormone, 1,25(OH) 2 D 3 . A second mitochondrial cytochrome P450 enzyme, the 24-hydroxylase (encoded by CYP24A1), can use both 25(OH)D and 1,25(OH) 2 D 3 as substrates, and is the first step in the inactivation pathway for these metabolites. Because of the direct role 1,25(OH) 2 D 3 plays in control of serum calcium levels, elevated levels of 1,25(OH) 2 D 3 block its synthesis and induce inactivation and accelerate catabolism 2 via induction of CYP24A1, in a classical negative feedback loop.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The first report that VDR actions could control cancer cell growth were discovered partly through serendipity, and partly through logical extension of other studies. Reports in the 1970s identified purified cell fractions that bound 1,25(OH) 2 D 3 with high affinity, 14 and encouraged investigators to begin to consider what were the molecular actions of the VDR in the classic tissues involved in calcium homeostasis, for example, skin, bone, intestine, and kidney. 15 In 1981, Kay Colston and coworkers 16 were first to demonstrate that 1α,25(OH) 2 D 3 at nanomolar concentrations inhibited human melanoma cell proliferation in vitro. That the workers used a cancer cell model was serendipitous; cancer cell models are more readily available to study in cell culture experiments than nonmalignant counterparts, and in this case 16 the cells chosen were available in an adjacent laboratory. Campbell and Trump In parallel, it was also known that retinoids, which are also small lipophilic molecules that target NRs, could drive cell differentiation, for exa...

Vitamin D deficiency and infection risk in kidney transplant recipients: A single‐center cohort study

“…The development of infectious complications after kidney transplantation (KT), which represents one of the leading causes of death with functioning graft, justifies the continuous investigation of novel clinical and biological risk markers. In addition to its well‐established role in regulating mineral balance and bone metabolism, vitamin D exerts a far larger number of “non‐classical” biological functions in extraskeletal tissues . Vitamin D deficiency has been accordingly associated with all‐cause and cardiovascular‐specific mortality in the general population, patients with end‐stage renal disease (ESRD), or KT recipients …”

“…In addition to its well-established role in regulating mineral balance and bone metabolism, vitamin D exerts a far larger number of "non-classical" biological functions in extraskeletal tissues. [1][2][3][4][5] Vitamin D deficiency has been accordingly associated with all-cause and cardiovascular-specific mortality in the general population, 6,7 patients with end-stage renal disease (ESRD), 8,9 or KT recipients. 10 Since the first observations linking sunlight exposure and tuberculosis susceptibility, 11 the immunomodulatory roles displayed by vitamin D have been extensively demonstrated.…”

Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow

“…Vitamin D (VD), whose availability modulates hematopoietic stem and progenitor cell (HSPC) production (Cortes et al, 2016), has potential antineoplastic properties (Campbell and Trump, 2017;Giovannucci et al, 2006). VD promotes cell differentiation in numerous tissues, such as prostate, breast, and the hematopoietic system (Jacobs et al, 2016;Samuel and Sitrin, 2008), through genomic activity that relies mostly on its association with VD receptor (VDR).…”

“…VD promotes cell differentiation in numerous tissues, such as prostate, breast, and the hematopoietic system (Jacobs et al, 2016;Samuel and Sitrin, 2008), through genomic activity that relies mostly on its association with VD receptor (VDR). In addition, VDR targets genes that are essential to cell cycle progression, another cancer feature (Campbell and Trump, 2017;Samuel and Sitrin, 2008). Therefore, VDR is a promising target in cancer therapy.…”

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

“…Hence, the addition of pro-epithelial agents to the standard treatment of EGFR-mutant NSCLC may not only extend the duration of initial response to TKIs but also improve their efficacy after malignant progression. Vitamin D, a secosteroid hormone recognized for its role in muscular-skeletal and immune physiology, is capable of promoting apoptosis and epithelial differentiation in a variety of preclinical tumor models [8][9][10][11][12]. The link between vitamin D status and lung cancer in the clinical setting remains controversial.…”