Calcitriol Induces Endoplasmic Reticulum Stress Response in Breast Cancer Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE53975 | GEO | 2015/01/01
SECONDARY ACCESSION(S): PRJNA234099
REPOSITORIES: GEO
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Project description:Calcitriol and transforming growth factors beta (TGF-β) are involved in several biological pathways such as cell proliferation, differentiation, migration and invasion. Their cellular effects could be similar or opposite depending on the genetic target, cell type and context. Despite the reported association of calcitriol deficiency and disruption of the TGF-β pathway in prostate cancer and the well-known independent effects of calcitriol and TGF-βs on cancer cells, there is limited information regarding the cellular effects of calcitriol and TGF-β in combination. In this study, we in vitro analyze the combinatory effects of calcitriol and TGF-β on cell growth and apoptosis using PC-3 and DU145 human prostate cancer cell lines. Using high-throughput microarray profiling of PC-3 cells upon independent and combinatory treatments, we identified distinct transcriptional landscapes of each intervention, with a higher effect established by the combinatorial treatment, following by TGF-β1 and later by calcitriol. A set of genes and enriched pathways converge among the treatments, mainly between the combinatory scheme and TGF-β1, but the majority were treatment-specific. Of note, CYP24A1, IGFBP3, SERPINE1, CDKN1A, NOX4 and UBE2D3 were significantly up-regulated upon the combinatorial treatment whereas CCNA1, members of the CT45A and APOBEC3 family were down-regulated. By public RNA signatures, we were able to confirm the regulation by the co-treatment over cell proliferation and cell cycle. We finally investigated the possible clinical impact of genes modulated by the combinatorial treatment using benchmark prostate cancer data. This comprehensive analysis reveals that the combinatory treatment impairs cell growth without affecting apoptosis and their combinatory actions might synergize and improved their individual effects to reprogram prostate cancer signaling.
2020-12-15 | GSE159116 | GEO
Project description:Objective: Induction of ER stress has been shown to promote NP cell apoptosis and disc degeneration. However, little is known about its regulation by hypoxia and its contribution to extracellular matrix homeostasis. Methods: NP cells were culture under hypoxia (1% O2) and normoxia (21% O2) to assess ER stress status. Tunicamycin and thapsigargin were used to induce canonical ER stress pathways and effects on cell secretome were assessed by proteomic analysis using mass spectrometry. The relevance of these findings to aging and degeneration was investigated by analyzing microarray data of NP tissues from aged mice (GSE134955) and degenerated human discs (GSE70362). Results: NP cells exhibited lower ER stress levels under hypoxia. ER stress inducers tunicamycin and thapsigargin promoted a canonical unfolded protein response. UPR further induced HIF-1 activity under hypoxia. NP cell secretome under ER stress showed an increased secretory pathway with a concomitant decrease in collagens, HAPLN1, and cell adhesion related proteins. Similar to our cell culture studies, NP tissues from aged mice and degenerated human discs presented higher levels of UPR markers and decreased levels of matrix components.
2020-12-03 | PXD019151 | Pride
Project description:Using pangenomic cDNA microarrays and qPCR techniques, we identified the genes regulated by calcitriol (1,25 (OH)D3, 10 nM) in dorsal root ganglia and/or Schwann cells. After 24 hours of calcitriol supplementation, we found a modified expression of many genes involved in axogenesis and myelination.
2012-04-07 | E-MEXP-3491 | biostudies-arrayexpress
Project description:Background: Breast cancer patients present lower 1,25(OH)2D3 or 25(OH)D3 serum levels than unaffected women. Although 1,25(OH)2D3 pharmacological concentrations of 1,25(OH)2D3 may exert antiproliferative effects in breast cancer cell lines, much uncertainty remains about the effects of calcitriol supplementation in tumor specimens in vivo. We have evaluated tumor dimension (ultrassonography), proliferative index (Ki67 expression), 25(OH)D3 serum concentration and gene expression profile, before and after a short term calcitriol supplementation (dose to prevent osteoporosis) to post-menopausal patients. Results: Thirty three patients with operable disease had tumor samples evaluated. Most of them (87.5%) presented 25(OH)D3 insufficiency (<30 ng/mL). Median period of calcitriol supplementation was 30 days. Although tumor dimension did not vary, Ki67 immunoexpression decreased after supplementation. Transcriptional analysis of 15 matched pre/post-supplementation samples using U133 Plus 2.0 GeneChip (Affymetrix) revealed 18 genes over-expressed in post-supplementation tumors. As a technical validation procedure, expression of four genes was also determined by RT-qPCR and a direct correlation was observed between both methods (microarray vs PCR). To further explore the effects of near physiological concentrations of calcitriol on breast cancer samples, an ex vivo model of fresh tumor slices was utilized. Tumor samples from another 12 post-menopausal patients were sliced and treated in vitro with slightly high concentrations of calcitriol (0.5nM), that can be attained in vivo, for 24 hours In this model, expression of PBEF1, EGR1, ATF3, FOS and RGS1 was not induced after a short exposure to calcitriol. Conclusions: In our work, most post-menopausal breast cancer patients presented at least 25(OH)D3 insufficiency. In these patients, a short period of calcitriol supplementation may prevent tumor growth and reduce Ki67 expression, probably associated with discrete transcriptional changes. This observation deserves further investigation to better clarify calcitriol effects in tumor behavior under physiological conditions. Post-menopausal patients with early stage breast cancer, in the absence of distant metastasis, were invited to take part in the study. This protocol was approved by the Institutional Ethics Committee, and a written informed consent was signed by all participants. Patients had blood and tumor samples collected during biopsy, and were prescribed calcitriol supplementation, (Rocaltrol)TM 0.50 g/day PO, as recommended for osteoporosis prevention. Tumor specimens obtained during biopsy (pre-supplementation) or breast surgery (post-supplementation) were hand dissected and samples with at least 70% tumor cells were further processed. Breast surgery followed in about one month
2012-02-18 | E-GEOD-35925 | biostudies-arrayexpress
Project description:Background: Breast cancer patients present lower 1,25(OH)2D3 or 25(OH)D3 serum levels than unaffected women. Although 1,25(OH)2D3 pharmacological concentrations of 1,25(OH)2D3 may exert antiproliferative effects in breast cancer cell lines, much uncertainty remains about the effects of calcitriol supplementation in tumor specimens in vivo. We have evaluated tumor dimension (ultrassonography), proliferative index (Ki67 expression), 25(OH)D3 serum concentration and gene expression profile, before and after a short term calcitriol supplementation (dose to prevent osteoporosis) to post-menopausal patients. Results: Thirty three patients with operable disease had tumor samples evaluated. Most of them (87.5%) presented 25(OH)D3 insufficiency (<30 ng/mL). Median period of calcitriol supplementation was 30 days. Although tumor dimension did not vary, Ki67 immunoexpression decreased after supplementation. Transcriptional analysis of 15 matched pre/post-supplementation samples using U133 Plus 2.0 GeneChip (Affymetrix) revealed 18 genes over-expressed in post-supplementation tumors. As a technical validation procedure, expression of four genes was also determined by RT-qPCR and a direct correlation was observed between both methods (microarray vs PCR). To further explore the effects of near physiological concentrations of calcitriol on breast cancer samples, an ex vivo model of fresh tumor slices was utilized. Tumor samples from another 12 post-menopausal patients were sliced and treated in vitro with slightly high concentrations of calcitriol (0.5nM), that can be attained in vivo, for 24 hours In this model, expression of PBEF1, EGR1, ATF3, FOS and RGS1 was not induced after a short exposure to calcitriol. Conclusions: In our work, most post-menopausal breast cancer patients presented at least 25(OH)D3 insufficiency. In these patients, a short period of calcitriol supplementation may prevent tumor growth and reduce Ki67 expression, probably associated with discrete transcriptional changes. This observation deserves further investigation to better clarify calcitriol effects in tumor behavior under physiological conditions.
2012-02-18 | GSE35925 | GEO
Project description:Dicer is a key endoribonuclease of the microRNA biogenetic machinery. Downregulation of Dicer has been associated with aberrant expression of microRNAs and the promotion of tumorigenesis. Calcitriol, the hormonal form of vitamin D3, increases microRNA expression in tumor cells, but the mechanism is not yet understood. Given the essential role of Dicer in microRNAs biogenesis, the purpose of this study was to evaluate whether this gene is a target for calcitriol and to explore the effects of this hormone on microRNA expression. Our findings demonstrate that calcitriol increased Dicer mRNA and protein in SiHa and HeLa cervical cancer cells, which expressed the vitamin D receptor. The inductive effect of calcitriol on Dicer mRNA was not observed in C33-A cells lacking this nuclear receptor. To explore the potential effect of Dicer upregulation by calcitriol on microRNA processing, we performed a microRNA profiling study in SiHa cells treated with calcitriol. The analysis of microRNA expression revealed that this hormone promotes the maturation of a subset of microRNAs with potential regulatory function in cancer pathways. Among these, miR-22 and miR-296-3p have already been associated with tumor-supressive effects. Our results suggest that Dicer upregulation by calcitriol could be associated, at least in part, with an increase in the maturation of a subset of tumor-suppressor microRNAs in cervical cancer cells.
2014-11-30 | GSE61829 | GEO
Project description:Glioblastoma is the most common primary brain cancer and is associated with poor survival and high rates of recurrent diseases. The median survival using standard radio-chemotherapy is 15 months and the 5-year survival rate is below 5%. It is hypothesized that treatment resistance, diffuse infiltration of the brain and disease recurrence is, at least in part, due to cancer cells that can obtain a transient, stem-like phenotype. These so-called glioma stem-like cells (GSCs) display pluripotency, express marker proteins associated with stem-cells and can replenish the tumor after treatment. Recently, we have shown that the hormonally active form of vitamin D3, calcitriol (1α,25(OH)2-vitamin D3), is active in a subset of GSCs and reduces traits of stemness. Here, we have employed a set of 8 GSCs that do not respond to calcitriol-treatment (No-responder) and the 8 strongest responders to calcitriol (High-responder) and compared to proteomes after treatment with 50 nM calcitriol for 48h.
2023-11-04 | PXD041634 | Pride
Project description:We aimed to explore the potential and mechanism of calcipotriol to regulate the hepatocellular transcriptome in comparison to calcitriol.
2018-06-14 | GSE106234 | GEO
Project description:Olanzapine is considered to induce dyslipidemia as an adversary effect in clinical practice. Critically, raised low-density lipoprotein levels and lowered high-density lipoprotein levels in the blood of patients are detected. The present study utilized three independent sources of clinical big data to analyze the drugs potent to prevent olanzapine-induced dyslipidemia, and vitamin D was found to be effective. To clarify the molecular mechanism of the influence of olanzapine and vitamin D, the culture of three cholesterol metabolism-related cells of mice, primary hepatocyte, primary adipocyte, and C2C12 cells (myocyte) were introduced to treat with olanzapine and vitamin D primary metabolites like calcifediol and calcitriol. RNA-seq was performed on these three types of cells to uncover the direct effects of olanzapine and vitamin D in cholesterol metabolism.
2023-01-13 | GSE221683 | GEO
Project description:Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24h incubation with Dermatophagoides farinae extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand (LPS) and calcitriol (1,25-dihydroxyvitamin D3), viability of the cells was analyzed using an MTT test and their secretion of IL-6, IL-10, CXCL8 and TGF-β1 was measured by ELISA. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA-sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion and co-administration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-β1 secretion could not be modulated by any of the stimuli. IL-6 and IL-10 could not be detected at the protein nor at the mRNA level. It can be concluded that D. farinae extract and TLR ligands augment the secretion of the pro-inflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by co-application of calcitriol and D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.
2020-04-14 | GSE148592 | GEO