Ornithine decarboxylase is sufficient for prostate tumorigenesis via androgen receptor signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE82179 | GEO | 2016/06/03
SECONDARY ACCESSION(S): PRJNA324259
REPOSITORIES: GEO
Similar Datasets
Project description:Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well-characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODC-overexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN.
| S-EPMC5225291 | biostudies-literature
Project description:Polyamines promote cellular proliferation, and their levels are controlled by ornithine decarboxylase antizyme 1 (Az1), through the proteasome-mediated, ubiquitin-independent degradation of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis. Az1-mediated degradation of other substrates such as cyclin D1, DNp73 and Mps1 also regulate cell growth and centrosome amplification. Collectively, the currently known six Az1-substrates are all linked with tumorigenesis. To understand if Az1-mediated protein degradation might play a key role in regulating cellular process associated with tumorigenesis, we employed quantitative proteomics to identify novel Az1 substrates. Here, we describe the identification of LIM domain and Actin-binding protein 1 (LIMA1), also known as epithelial protein lost in neoplasm (EPLIN), as a new target of Az1. Interestingly, between the two isoforms of EPLIN-Alpha and -Beta, only EPLIN-Beta is the substrate of Az1, degraded in an ubiquitination-independent manner. Absence of Az1 led to elevated EPLIN-Beta levels, which caused enhanced cellular migration of Az1-/- cells. Consistently, higher levels of LIMA1 correlated with poorer overall survival of colorectal cancer patients. Taken together, this study identifies EPLIN-Beta as a novel Az1 substrate regulating cellular migration.
2023-06-08 | PXD039865 | Pride
Project description:Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners. Interestingly, three major subgroups of genomic subcomplexes were identified, where selective gain of function for AR genomic action in tumorigenesis was found, dictated by FOXA1 and HOXB13. In summary, by combining proteomic and genomic approaches we reveal subclasses of AR transcriptional complexes, differentiating normal AR behavior from the oncogenic state. In this process, the expression of AR interactors has key roles by reprogramming the AR cistrome and interactome in a genomic location-specific manner.
2017-10-27 | PXD008056 | Pride
Project description:Aberrant androgen receptor (AR)-mediated transcription is a critical driver in progression of human prostate cancer. It's known that different doses of androgens can elicit differential transcriptional and proliferative responses in prostate-tumor cells. Here, we set out to examine the androgenic regulation of glycoprotein expression in the membrane fraction of prostate-tumor cells that could serve as mediators or markers of androgen-induced proliferative responses observed in prostate-tumor cells. A bioanalytical workflow involving lectin-affinity chromatography and label-free quantitative mass spectrometry was used to identify androgen-sensitive glycomembrane protein expression associated with androgen-mediated proliferation. This study would facilitate the identification of surface membrane proteins involved in androgen-mediated proliferation and provide potential therapeutic targets in the detection treatment of proliferation prostate-tumors.
2022-03-01 | PXD002913 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDA) cells have a distinct dependence on de novo ornithine synthesis from glutamine via ornithine aminotransferase (OAT), which supports polyamine synthesis and is required for tumor growth. This directional OAT activity is normally largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginase (ARG) to generate arginine-derived ornithine, the substrate for polyamine synthesis. This dependence associates with arginine depletion in PDA tumor microenvironment, and is driven by mutant KRAS, which induces the expression of OAT and polyamine synthesis enzymes, including the rate-limiting enzyme ornithine decarboxylase-1 (ODC1). Loss of OAT, but not ARG2, largely mimics loss of ODC1, altering the transcriptional profiles in PDA cells, which in turn correlate with alterations in open chromatin states.
2023-01-01 | GSE193411 | GEO
Project description:Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against C. rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that cell-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as augments autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.
2022-10-06 | GSE214152 | GEO
Project description:Ornithine decarboxylase is sufficient for prostate tumorigenesis via androgen receptor signaling
| PRJNA324259 | ENA
Project description:Ornithine Decarboxylase Activity in Gastric Epithelial Cells Contributes to the Pathogenesis of Helicobacter pylori
| PRJNA753859 | ENA
Project description:Progression to androgen independent is the main cause of death in prostate cancer, and the mechanism is still unclear. By reviewing the expression profiles of 26 prostate cancer samples in a holistic view, we found a group of genes differentially expressed in androgen independent compared with androgen dependent groups (p value< 0.01, t test). Focusing on apoptosis, proliferation, hormone and angiogenesis, we found a group of genes such as thioredoxin domain containing 5 (TXNDC5), tumor necrosis factor receptor superfamily, member 10a (TNFRSF10A), ribosomal protein S19 (RPS19) and Janus kinase 2 (JAK2) up-regulated in androgen independent prostate cancer, which could play important roles in the transition from androgen dependent to androgen independent and could be biomarkers of prognosis. The main aim was comparing the androgen dependent and androgen independent prostate cancer to identify differentially expressed genes. In addition, we added several normal prostate tissue sample for comparisons. Totally 29 experiments were performed without replicates. 3 for normal prostate tissue, 8 for androgen independent cancer and 18 for androgen dependent prostate cancer. In all experiments, the reference samples are common reference, a pool with unrelated fetal tissues.
2007-09-09 | E-GEOD-5803 | biostudies-arrayexpress
Project description:Androgens are a prequisite for the development of human prostate and prostate cancer. Androgen action is mediated via androgen receptor. Androgen ablation therapy is used for the treatment of metastasized prostate cancer. The aim of the study was to identify genes differentially expressed in benign human prostate, prostate cancer and in prostate tissue three days after castration. These genes are potential diagnostic and therapeutic targets for prostate cancer and benign prostatic hyperplasia. We used microarrays to examine the gene expression profiles in benign prostate adjacent to prostate cancer and prostate cancer in radical prostatectomy specimens and in prostate tissue samples taken 3 days after surgical castration performed for treatment of prostate cancer.
2012-06-20 | GSE32982 | GEO