Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Androgen receptor survival signaling is blocked by anti-beta2-microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells.

ABSTRACT: A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5'-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-beta2-microglobulin monoclonal antibody (beta2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. beta2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, beta2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, beta2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the beta2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing beta2M by beta2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression.

SUBMITTER: Huang WC

PROVIDER: S-EPMC2832945 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Beta2-microglobulin signaling blockade inhibited androgen receptor axis and caused apoptosis in human prostate cancer cells.

Project description:beta2-Microglobulin (beta2M) has been shown to promote osteomimicry and the proliferation of human prostate cancer cells. The objective of this study is to determine the mechanism by which targeting beta2M using anti-beta2M antibody inhibited growth and induced apoptosis in prostate cancer cells.Polyclonal and monoclonal beta2M antibodies were used to interrupt beta2M signaling in human prostate cancer cell lines and the growth of prostate tumors in mice. The effects of the beta2M antibody on a survival factor, androgen receptor (AR), and its target gene, prostate-specific antigen (PSA) expression, were investigated in cultured cells and in tumor xenografts.The beta2M antibody inhibited growth and promoted apoptosis in both AR-positive and PSA-positive, and AR-negative and PSA-negative, prostate cancer cells via the down-regulation of the AR in AR-positive prostate cancer cells and directly caused apoptosis in AR-negative prostate cancer cells in vitro and in tumor xenografts. The beta2M antibody had no effect on AR expression or the growth of normal prostate cells.beta2M downstream signaling regulates AR and PSA expression directly in AR-positive prostate cancer cells. In both AR-positive and AR-negative prostate cancer cells, interrupting beta2M signaling with the beta2M antibody inhibited cancer cell growth and induced its apoptosis. The beta2M antibody is a novel and promising therapeutic agent for the treatment of human prostate cancers.

| S-EPMC3032570 | biostudies-literature

Anti beta2-microglobulin monoclonal antibodies induce apoptosis in myeloma cells by recruiting MHC class I to and excluding growth and survival cytokine receptors from lipid rafts.

Project description:We recently showed that monoclonal antibodies (mAbs) against beta2-microglobulin (beta2M) have a remarkably strong apoptotic effect on myeloma cells. The mAbs induced apoptosis by recruiting major histocompatibility complex (MHC) class I to lipid rafts, activated c-Jun N-terminal kinase (JNK), and inhibited phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways. Growth and survival cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-I), which could protect myeloma cells from dexamethasone-induced apoptosis, did not affect mAb-mediated cell death. This study was undertaken to elucidate the mechanisms underlying anti-beta2M mAb-induced PI3K/Akt and ERK inhibition and the inability of IL-6 and IGF-I to protect myeloma cells from mAb-induced apoptosis. We focused on lipid rafts and confirmed that these membrane microdomains are required for IL-6 and IGF-I signaling. By recruiting MHC class I into lipid rafts, anti-beta2M mAbs excluded IL-6 and IGF-I receptors and their substrates from the rafts. The mAbs not only redistributed the receptors in cell membrane, but also abrogated IL-6- or IGF-I-mediated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), PI3K/Akt, and Ras/Raf/ERK pathway signaling, which are otherwise constitutively activated in myeloma cells. Thus, this study further defines the tumoricidal mechanism of the mAbs and provides strong evidence to support the potential of these mAbs as therapeutic agents for myeloma.

| S-EPMC2018676 | biostudies-literature

Role for beta2-microglobulin in echovirus infection of rhabdomyosarcoma cells.

Project description:A monoclonal antibody (MAb) that blocks most echoviruses (EVs) from infecting rhabdomyosarcoma (RD) cells has been isolated. By using the CELICS cloning method (T. Ward, P. A. Pipkin, N. A. Clarkson, D. M. Stone, P. D. Minor, and J. W. Almond, EMBO J. 13:5070-5074, 1994), the ligand for this antibody has been identified as beta2-microglobulin (beta2m), the 12-kDa protein that associates with class I heavy chains to form class I HLA complexes. A commercial MAb (MAb 1350) against beta2m was also found to block EV7 infection without affecting binding to its receptor, DAF, or replication of EV7 viral RNA inside cells. Entry of EV7 into cells was reduced by only 30% by antibody and cytochalasin D, an inhibitor of endocytosis mediated by caveolae and clathrin-coated pits, but was not significantly reduced by sodium azide. The block to virus entry by cytochalasin D was additive to the block induced by antibody. We suggest that EV7 rapidly enters into a multicomponent receptor complex prior to entry into cells and that this initial entry event requires beta2m or class I HLA for infection to proceed.

| S-EPMC110159 | biostudies-literature

Atypical haemochromatosis: phenotypic spectrum and beta2-microglobulin candidate gene analysis.

Project description:Beta2-microglobulin was investigated in atypical haemochromatosis patients not homozygous for the C282Y mutation of HFE (OMIM *235200), because the HFE protein binds beta2-microglobulin, and in mice beta2-microglobulin gene knockout causes hepatic iron overload. Six unrelated patients with atypical haemochromatosis were studied. Five patients had normal HFE coding sequence and the sixth was heterozygous for C282Y. We show that the spectrum of atypical haemochromatosis includes two distinct familial forms: juvenile haemochromatosis (OMIM *602390) and a novel form of familial iron overload, with apparently autosomal dominant inheritance, predominant Kupffer cell siderosis, and possible minimal dyserythropoiesis on bone marrow examination. Serial serum beta2-microglobulin estimation showed normal levels in all patients. Southern blot analysis showed normal beta2-microglobulin gene structure, excluding major gene rearrangement. Several corrections to the published beta2-microglobulin sequence were identified, but all six patients had normal beta2-microglobulin sequence. Western blot analysis of serum showed beta2-microglobulin protein of normal size. In conclusion, we found no evidence to implicate beta2-microglobulin mutation in atypical haemochromatosis. Two forms of familial iron overload appear unrelated to either HFE or beta2-microglobulin. Linkage studies are required to identify the genes involved, which may encode novel proteins crucial to the regulation of iron metabolism. Identification of these loci will aid the diagnosis, counselling, and treatment of iron overload disorders.

| S-EPMC1734400 | biostudies-literature

Inhibition of beta2-microglobulin amyloid fibril formation by alpha2-macroglobulin.

Project description:The relationship between various amyloidoses and chaperones is gathering attention. In patients with dialysis-related amyloidosis, ?(2)-macroglobulin (?2M), an extracellular chaperone, forms a complex with ?(2)-microglobulin (?2-m), a major component of amyloid fibrils, but the molecular mechanisms and biological implications of the complex formation remain unclear. Here, we found that ?2M substoichiometrically inhibited the ?2-m fibril formation at a neutral pH in the presence of SDS, a model for anionic lipids. Binding analysis showed that the binding affinity between ?2M and ?2-m in the presence of SDS was higher than that in the absence of SDS. Importantly, SDS dissociated tetrameric ?2M into dimers with increased surface hydrophobicity. Western blot analysis revealed that both tetrameric and dimeric ?2M interacted with SDS-denatured ?2-m. At a physiologically relevant acidic pH and in the presence of heparin, ?2M was also dissociated into dimers, and both tetrameric and dimeric ?2M interacted with ?2-m, resulting in the inhibition of fibril growth reaction. These results suggest that under conditions where native ?2-m is denatured, tetrameric ?2M is also converted to dimeric form with exposed hydrophobic surfaces to favor the hydrophobic interaction with denatured ?2-m, thus dimeric ?2M as well as tetrameric ?2M may play an important role in controlling ?2-m amyloid fibril formation.

| S-EPMC3059021 | biostudies-literature

Unexpected beta2-microglobulin sequence diversity in individual rainbow trout.

Project description:For mammals beta2-microglobulin (beta2m), the light chain of major histocompatibility complex (MHC) class I molecules, is invariant (or highly conserved) and is encoded by a single gene unlinked to the MHC. We find that beta2m of a salmonid fish, the rainbow trout (Oncorhynchus mykiss), does not conform to the mammalian paradigm. Ten of 12 randomly selected beta2m cDNA clones from an individual fish have different nucleotide sequences. A complex restriction fragment length polymorphism pattern is observed with rainbow trout, suggesting multiple beta2m genes in the genome, in excess of the two genes expected from the ancestral salmonid tetraploidy. Additional duplication and diversification of the beta2m genes might have occurred subsequently. Variation in the beta2m cDNA sequences is mainly at sites that do not perturb the structure of the mature beta2m protein, showing that the observed diversity of the trout beta2m genes is not primarily a result of pathogen selection.

| S-EPMC39709 | biostudies-other

Equilibrium unfolding thermodynamics of beta2-microglobulin analyzed through native-state H/D exchange.

Project description:The exchange rates for the amide hydrogens of beta(2)-microglobulin, the protein responsible for dialysis-related amyloidosis, were measured under native conditions at different temperatures ranging from 301 to 315 K. The pattern of protection factors within different regions of the protein correlates well with the hydrogen-bonding pattern of the deposited structures. Analysis of the exchange rates indicates the presence of mixed EX1- and EX2-limit mechanisms. The measured parameters are consistent with a two-process model in which two competing pathways, i.e., global unfolding in the core region and partial openings of the native state, determine the observed exchange rates. These findings are analyzed with respect to the amyloidogenic properties of the protein.

| S-EPMC2710044 | biostudies-literature

TRIM36, a novel androgen-responsive gene, enhances anti-androgen efficacy against prostate cancer by inhibiting MAPK/ERK signaling pathways.

Project description:Hormone therapy drugs, such as bicalutamide and enzalutamide, directed against prostate cancer focus on androgen receptor (AR) signaling and are initially effective, but the disease progresses to lethality as resistance to these drugs develops. A method to prolong the drug response time and improve the drug efficacy is still unavailable. TRIM36 was reported as a novel androgen signaling target gene and is upregulated in prostate cancer. In this study, we found that 63.4% (64/95) of PCa in TMA expressed the TRIM36 protein. Interestingly, patients with negative TRIM36 expression had a shorter biochemical recurrence-free survival. TRIM36 expression was significantly associated with the Gleason score (P?=?0.005), delayed prostate cancer cell cycle progression and inhibited cell proliferation in vitro and in vivo, and these effects were mediated via inhibition of the MAPK/ERK phosphorylation pathway. Remarkably, we found that rescuing the expression of TRIM36 during anti-androgen therapy could improve the drug efficacy. Collectively, TRIM36 is a novel androgen-responsive gene, and it dramatically enhanced the efficacy of anti-androgen drugs against prostate cancer.

| S-EPMC5833828 | biostudies-other

Magic angle spinning NMR analysis of beta2-microglobulin amyloid fibrils in two distinct morphologies.

Project description:Beta(2)-microglobulin (beta(2)m) is the major structural component of amyloid fibrils deposited in a condition known as dialysis-related amyloidosis. Despite numerous studies that have elucidated important aspects of the fibril formation process in vitro, and a magic angle spinning (MAS) NMR study of the fibrils formed by a small peptide fragment, structural details of beta(2)m fibrils formed by the full-length 99-residue protein are largely unknown. Here, we present a site-specific MAS NMR analysis of fibrils formed by the full-length beta(2)m protein and compare spectra of fibrils prepared under two different conditions. Specifically, long straight (LS) fibrils are formed at pH 2.5, while a very different morphology denoted as worm-like (WL) fibrils is observed in preparations at pH 3.6. High-resolution MAS NMR spectra have allowed us to obtain (13)C and (15)N resonance assignments for 64 residues of beta(2)m in LS fibrils, including part of the highly mobile N-terminus. Approximately 25 residues did not yield observable signals. Chemical shift analysis of the sequentially assigned residues indicates that these fibrils contain an extensive beta-sheet core organized in a non-native manner, with a trans-P32 conformation. In contrast, WL fibrils exhibit more extensive dynamics and appear to have a smaller beta-sheet core than LS fibrils, although both cores seem to share some common elements. Our results suggest that the distinct macroscopic morphological features observed for the two types of fibrils result from variations in structure and dynamics at the molecular level.

| S-EPMC2919207 | biostudies-literature

Expression, purification, crystallization and preliminary X-ray diffraction analysis of grass carp beta2-microglobulin.

Project description:Beta(2)-microglobulin (beta(2)m) is an essential subunit of MHC I molecules; it stabilizes the structure of MHC I and plays a pivotal role in coreceptor recognition. To date, structures of beta(2)m have been solved for three different mammals: human, mouse and cattle. In order to illuminate the molecular evolutionary origin of beta2m, an understanding of its structure in lower vertebrates becomes important. Here, grass carp (Ctenopharyngodon idellus) beta(2)m (Ctid-beta(2)m) was expressed, purified and crystallized. Diffraction data were collected to a resolution of 2.5 A. The crystal belongs to space group P2(1)2(1)2(1), with unit-cell parameters a = 38.72, b = 40.65, c = 71.12 A. The Matthews coefficient and the solvent content were calculated to be 2.56 A Da(-1) and 52.07%, respectively, for one molecule per asymmetric unit. The structure has been solved by molecular replacement using monomeric human beta(2)m as a model.

| S-EPMC2374163 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data