Suppression of Death Receptor-mediated Apoptosis by 1,25-Dihydroxyvitamin D3 Revealed by Microarray Analysis

Abstract

Vitamin D 3 (VD)2 is a steroid hormone best known for its role in calcium homeostasis. Its deficiency causes rickets in children and osteomalacia in adults. VD also regulates the proliferation and differentiation of normal and malignant cells of many tissue types. Because sunlight controls the first step of VD synthesis, namely, the photoconversion of 7-dehydrocholesterol to vitamin D 3 (1), the hormone is considered a "sun" medicine that is effective for the treatment and/or prevention of type II rickets, osteoporosis, autoimmune disorders, as well as epithelial cancers of many types.Ovarian cancer (OCa) is a fatal disease with an overall 5-year survival rate of about 40%. OCa mortality and incidence rates are lower in countries within 20 degrees of the equator (2) where there is a high amount of sunlight. In the United States, women between the ages of 45 and 54 living in the North have 5 times the OCa mortality rate of women living in Southern states (3). The inverse correlation between sunlight exposure and OCa mortality indicates that decreased synthesis of VD may contribute to OCa initiation and/or progression. This idea has been further substantiated by recent studies (4 -7) showing that 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), the active form of VD, inhibits the growth of multiple OCa cell lines (4 -6) and OVCAR3 tumor xenografts in nude mice (7).Effects of VD are mediated through the vitamin D receptor (8), which is a member of the steroid/thyroid receptor superfamily of ligand-regulated transcription factors. In response to the activation by 1,25-(OH) 2 D 3 , the receptor recruits multiple co-activators, including members of the p160 SRC family (9), which are associated with histone acetyltransferase activity, and the DRIP complex (10), which serves as a mediator between the vitamin D receptor and RNA polymerase II complex. Recent studies (11) have suggested that the anti-tumor activity of VD is mediated through its effect on gene transcription. In OCa cells, we have shown that the transcriptional up-regulation of GADD45 is essential for the 1,25-(OH) 2 D 3 -induced cell cycle arrest at the G 2 /M checkpoint (4). 1,25-(OH) 2 D 3 also increases p27 protein stability in OCa cells through down-regulation of Skp2 and cyclin E mRNA to induce cell cycle arrest at the G 1 /S checkpoint (6). These studies suggest that the action of 1,25-(OH) 2 D 3 through the nuclear activation of vitamin D receptor is important for the anti-tumor activity of the hormone in OCa.Because the anti-tumor activity of 1,25-(OH) 2 D 3 is mediated through regulation of gene expression, a more complete understanding of the mechanism underlying 1,25-(OH) 2 D 3 action in OCa cells necessitates identification of changes in gene expression induced by the hormone. In the present study, we profile transcriptional changes in OVCAR3 cells induced by 1,25-(OH) 2 D 3 using multiple independent microarray analyses. We concentrated our subsequent analysis to a few apoptosis-related genes from this list. Our studies reveal that 1,25-(OH) 2 D 3...

Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells

“…Although caspase cleavage and the action of other apoptosis-related molecules usually occurs within 24 hours or less, it has been shown that vitamin D acts much more slowly to effect apoptosis. For example, Zhang and colleagues (53,54) have shown the strongest apoptotic response at 6 days following treatment using a vitamin D analog in several cell lines. Mathiasen and colleagues (55) also showed peak vitamin D-induced apoptosis at 6 to 7 days posttreatment.…”

Differential expression of prohibitin is correlated with dual action of Vitamin D as a proliferative and antiproliferative hormone in breast epithelial cells

“…In the literature vitamin D is often reported to inhibit both proliferation and apoptosis in cancer cells [9,10]. However the detailed signaling pathway for such dual effects has been poorly understood.…”

Vitamin D in cancer chemoprevention

“…This phenomenon may results in an inhibition of IFN-g induced activation and potentiation of lysosomal activity of macrophages, recruitment of autophagic proteins, and, ultimately, may lead to a decrease of autophagy Wu and Sun (2011) NF-kB expression (?) Bao et al (2010), Krishnan and Feldman (2010), Tse et al (2010), andJanjetovic et al (2011) Induced expression of thioredoxin reductase 1 (TXNRD1) Swami et al (2003), Peehl et al (2004), Kovalenko et al (2010) Antioxidant defense and DNA repair Increased production of superoxide dismutase 1 and 2 (SOD1 and SOD2) in prostate epithelial cells (PECs) and in androgen-sensitive prostate cancer cells (LNCaP) Peehl et al (2004) and Lambert et al (2006) Increase of glucose-6-phosphate dehydrogenase (G6PDH) expression levels Zhang et al (2005), Bao et al (2008), and Kovalenko et al (2010) Induction of nuclear factor erythroid-derived 2-like 2 (NFE2L2) transcription factor that controls the gene expression of several enzymes of the antioxidants systems such as glutathione peroxidase (GPX) 3, heme oxygenase 1 (HMOX-1), and aldo-keto reductase 1C2(AKR1C2)…”

“…In addition, 1,25(OH) 2 D 3 has been shown to increase the production of superoxide dismutase 1 (SOD1) and 2 (SOD2) in prostate epithelial cells (PECs) and in androgen-sensitive prostate cancer cells (LNCaP), respectively (Lambert et al, 2006;Peehl et al, 2004). Furthermore, other in vitro observations show that the treatment of the human prostate epithelial cell line RWPE-1, and that of BPH-1 benign prostatic hyperplasia (BPH) epithelial cell line or OVCAR3 ovarian carcinoma cell line, with 1,25(OH) 2 D 3 , increases the intracellular levels of glucose-6-phosphate dehydrogenase (G6PDH), an enzyme which regulates the intracellular levels glutathione (Bao et al, 2008;Kovalenko et al, 2010;Zhang et al, 2005). This effect ultimately protects cells from apoptosis induced by H 2 O 2.…”