LACTB suppress glioma growth by promoting Hsc70-mediated degradationERBB3
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Jianguo Xu
PROVIDER: PXD060580 | iProX | Fri Feb 07 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:Abnormal lipid metabolism is a hallmark of tumor and represents an anti-cancer strategy. β-lactamase like protein (LACTB) is a novel tumor suppressor, but the biological function and the involved mechanism in glioma remain unclear. Here, we show that LACTB overexpression suppresses glioma growth while LACTB knockdown shows the opposite effect. By RNA-sequencing and untargeted lipidomics analysis, we find that LACTB overexpression inhibits the lipid synthesis of glioma cells. Mechanistically, LACTB downregulates ERBB3 and inhibits PI3K/AKT/mTOR signaling, which restrains the lipogenesis of tumor cells. We further uncover that LACTB overexpression decreases the protein stability of ERBB3 by lysosomal degradation. LACTB promotes the interaction of ERBB3 and Hsc70 to facilitate ERBB3 degradation in lysosome. Finally, we show that targeting LACTB/ERBB3 axis significantly suppresses glioma growth in the mouse model. Therefore, our study reveals the antitumoral role of LACTB in glioma and the LACTB/ERBB3 axis represents a potential new therapeutic target for this tumor.
2026-02-05 | GSE288782 | GEO
Project description:The knock down of T-cell intracellular antigen (TIA) proteins enhances the acquisition of aberrant cellular phenotypes promoting uncontrolled cell and tumor growth. Hereby, we report that inducible expression of either TIA1 or TIAR in human embryonic kidney (HEK293) cells represses cell proliferation. Mechanistically, the sustained expression of either TIA1 or TIAR protein abolishes endogenous TIA1/TIAR protein expression via regulating splicing of their own pre-mRNAs. This event is concomitant with cell cycle arrest and cell death by apoptosis. Based on genome-wide analysis of the transcript expression patterns in HuR-, TIA1- or TIAR-expressing HEK293 cells, we found regulatory links among the up-regulation on a select subset of p53 pathway genes involved in G1/S cell-cycle and apoptosis control. Finally, nude mice injected with TIA1- or TIAR-expressing HEK293 cells decrease, and even abolishing, the growth of tumor xenografts relative to control cells. Collectively, these observations show that TIA proteins can function as tumor suppressor genes. Two independent biological replicates were performed per sample type. Agilent SurePrint G3 Human Gene Expression 8x60K v2 array were used in all cases (single-channel hybridizations)
2015-03-05 | E-GEOD-51500 | biostudies-arrayexpress
Project description:The knock down of T-cell intracellular antigen (TIA) proteins enhances the acquisition of aberrant cellular phenotypes promoting uncontrolled cell and tumor growth. Hereby, we report that inducible expression of either TIA1 or TIAR in human embryonic kidney (HEK293) cells represses cell proliferation. Mechanistically, the sustained expression of either TIA1 or TIAR protein abolishes endogenous TIA1/TIAR protein expression via regulating splicing of their own pre-mRNAs. This event is concomitant with cell cycle arrest and cell death by apoptosis. Based on genome-wide analysis of the transcript expression patterns in HuR-, TIA1- or TIAR-expressing HEK293 cells, we found regulatory links among the up-regulation on a select subset of p53 pathway genes involved in G1/S cell-cycle and apoptosis control. Finally, nude mice injected with TIA1- or TIAR-expressing HEK293 cells decrease, and even abolishing, the growth of tumor xenografts relative to control cells. Collectively, these observations show that TIA proteins can function as tumor suppressor genes.
2015-03-05 | GSE51500 | GEO
Project description:BackgroundHigh-grade gliomas are malignant brain tumors characterized by aggressiveness and resistance to chemotherapy. Prognosis remains dismal, highlighting the need to identify novel molecular dependencies and targets. Ribosome biogenesis (RiBi), taking place in the nucleolus, represents a promising target as several cancer types rely on high RiBi rates to sustain proliferation. Publicly available transcriptomics data of glioma patients revealed a positive correlation between RiBi rates and histological grades. We, therefore, hypothesized that glioma cells could be susceptible to RiBi inhibition.MethodsTranscriptomics data from glioma patients were analyzed for RiBi-related processes. BMH-21, a small molecule inhibitor of RNA pol I transcription, was tested in adult and pediatric high-grade glioma cell lines and a zebrafish transplant model. Cellular phenotypes were evaluated by transcriptomics, cell cycle analysis, and viability assays. A chemical synergy screen was performed to identify drugs potentiating BMH-21-mediated effects.ResultsBMH-21 reduced glioma cell viability, induced apoptosis, and impaired the growth of transplanted glioma cells in zebrafish. Combining BMH-21 with TMZ potentiated cytotoxic effects. Moreover, BMH-21 synergized with Fibroblast Growth Factor Receptor (FGFR) inhibitor (FGFRi) Erdafitinib, a top hit in the chemical synergy screen. RiBi inhibition using BMH-21, POLR1A siRNA, or Actinomycin D revealed engagement of the FGFR-FGF2 pathway. BMH-21 downregulated FGFR1 and SOX2 levels, whereas FGF2 was induced and released from the nucleolus.ConclusionsThis study conceptualizes the implementation of RiBi inhibition as a viable future therapeutic strategy for glioma and reveals an FGFR connection to the cellular response upon RiBi inhibition with potential translational value.
| S-EPMC10237440 | biostudies-literature
Project description:LACTB inhibits lipid synthesis to suppress glioma growth by promoting Hsc70-mediated ERBB3 degradation
| PRJNA1219396 | ENA
Project description:PCBP2, a member of the poly(C)-binding protein (PCBP) family, is involved in posttranscriptional and translational regulation by interacting with single-stranded poly(C) motifs in target mRNAs. Recent studies have shown that PCBP2 is overexpressed and plays an important role in human cancers, including glioma. However, the molecular basis for its up-regulation remains poorly understood. Here, we show that microRNA-214 (miR-214) interacts with the 3'-untranslated region of PCBP2 mRNA and induces its degradation, leading to reductions in its protein expression. As a result, overexpression of miR-214 mimics significantly inhibited, while its antisense oligos proliferation and growth of glioma cells. Restoration of PCBP2 remarkably reversed the tumor-suppressive effects of miR-214 on cell proliferation and growth. In summary, our data indicate that miR-214 may function as tumor suppressor in glioma by targeting PCBP2.
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Project description:We developed a nanobiologic platform that is designed to induce trained immunity. Through extensive in vitro screening, involving stability measurements and training assays on human and murine monocytes, as well as in vivo mouse biodistribution experiments, a bone marrow-avid nanobiologic lead candidate, named MTP10-HDL, was identified. MTP10-HDL’s potent anti-tumor capabilities were established in a dose response study. We found that these anti-tumor effects are the result of trained immunity-induced myelopoiesis, caused by the activation of hematopoietic stem cells and multipotent progenitors in the bone marrow. Moreover, we established that MTP10-HDL treatment overcomes the immunosuppressive tumor microenvironment (TME) by reducing the number of myeloid-derived suppressor cells and tumor associated macrophages. The immunologically rebalanced TME potentiated concurrent checkpoint blockade therapy, resulting in augmented anti-tumor efficacy. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response, as a monotherapy or in combination with checkpoint blockade. We examined MTP10-HDL’s effect on hematopoiesis to elucidate the mechanism underlying its anti-tumor effect in C57BL/6 mice without tumors. We performed RNA sequencing (RNA-seq) to investigate HSC activation. Bone marrow from treated and untreated mice was harvested and the HSCs were isolated by flow sorting.
2019-02-21 | GSE126793 | GEO
Project description:EZH2 is crucial for the progression of prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) through upregulation and activation of progenitor genes, as well as androgen receptor (AR)-target genes. However, the mechanisms by which EZH2 is regulated in PCa and CRPC remain elusive. Here we report that EZH2 is post-transcriptionally regulated by SKP2 in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of Skp2, Ezh2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) and Pten null mouse prostate tissues. Loss of Skp2 resulted in a striking decrease of Ezh2 levels in Pten/Trp53 double-null MEFs and in prostate tumors of Pten/Trp53 double-null mutant mice. SKP2 knockdown decreased EZH2 levels in human PCa cells through upregulation of TRAF6-mediated and lysine(K) 63-linked ubiquitination of EZH2 for degradation. Ectopic expression of TRAF6 promoted the K63-linked ubiquitination of EZH2 to decrease EZH2 and H3K27me3 levels in PCa cells. In contrast, TRAF6 knockdown resulted in a reduced EZH2 ubiquitination with an increase of EZH2 and H3K27me3 levels in PCa cells. Furthermore, the catalytically dead mutant TRAF6 C70A abolished the TRAF6-mediated polyubiquitination of recombinant human EZH2 in vitro. Most importantly, a concurrent elevation of Skp2 and Ezh2 was found in CRPC tumors of Pten/Trp53 mutant mice, and expression levels of SKP2 and EZH2 were positively correlated in human PCa specimens. Taken together, our findings revealed a novel mechanism on EZH2 ubiquitination and an important signaling network of SKP2-TRAF6-EZH2/H3K27me3, and targeting SKP2-EZH2 pathway may be a promising therapeutic strategy for CRPC treatment.
| S-EPMC5724960 | biostudies-literature
Project description:<p><strong>BACKGROUND:</strong> The coevolution and interaction between plants and microorganisms have long been a subject of significant research interest. Dark septate endophytes (DSE) have garnered great attention in contemporary research due to their functional diversity, in vitro cultivation ability, and ability to establish symbiotic associations with host plants. In the present study, three DSE strains, namely <em>Acrocalymma vagum</em>, <em>Zopfiella marina</em>, and <em>Phoma herbarum</em>, which were obtained from the roots of <em>Astragalus membranaceus</em>, were introduced into maize plants through inoculation. We evaluated the effects of DSE inoculation on maize growth and root secretion activity through a multi omics methods, and proposed mechanisms for 'internal pathways' and 'external pathways'.</p><p><strong>RESULTS:</strong> The findings indicated that A. vagum exhibited superior growth-promoting ability on maize compared to <em>Z. marina</em> and <em>P. herbarum</em>.GO and KEGG enrichment analysis found that <em>A. vagum</em> inoculation resulted in significant enrichment of differentially expressed genes in annotation functions related to hormone regulation and lipid metabolism. A. vagum inoculation revealed that the gene pathways involved in plant hormone signaling and plant pathogen interactions play a crucial role in promoting host growth, and <em>A. vagum</em> inoculation group exhibited the highest number of differentially expressed genes, the most intricate protein-protein interaction (PPI) model, and the most pronounced relationship between differentially expressed genes. After the inoculation of <em>A.vagum</em>, the levels of salicylic acid, zeatin, and IAA in maize plants significantly increased. Additionally, the diversity and abundance of endophytic fungi, as well as the proportion of harmful bacteria and beneficial fungi, had significantly increased. Compared with <em>Z. marina</em> and <em>P. herbarum</em>, the net photosynthetic rate (Pn) and stomatal conductance (Gs) of <em>A.vagum</em> inoculated plants significantly increased. Inoculation with <em>A.vagum</em> could enhance the ability of corn roots to secrete lipids, sugars, and amino acids, resulted in a notable augmentation of beneficial bacteria and fungi, accompanied by a significant reduction in the proportion of harmful bacteria in the rhizosphere soil, such as <em>Fusarium solani</em> and <em>Fusarium lacertarum</em>, exhibited significant inhibition, whereas <em>Bacillus niabensis</em> and <em>Bacillus nealsonii</em> demonstrated enrichment trends. Soil pH, organic matter, available potassium content, acid phosphatase, alkaline phosphatase and urease activity exhibited significant increases following the inoculation of <em>A. vagum</em>. Variance decomposition and structural equation modeling (SEM) analysis indicated that the 'internal pathway', maize growth is mainly influenced by the interaction of endogenous hormones, endophytic microorganisms, and photosynthetic parameters, whereas within the 'external pathway', the interaction between soil microorganisms and soil physicochemical properties exerted a dominant influence. Compared with the <em>Z. marina</em> and <em>P. herbarum</em> inoculation, <em>A. vagum</em> inoculation showed a more significant impact on maize growth, both in terms of 'internal pathway' and 'external pathway', in terms of pathway level and quantity.</p><p><strong>CONCLUSIONS:</strong> These findings provide a new perspective for understanding the potential mechanisms of 'microbe-plant' interactions and also contribute to the exploration of targeted functional microorganisms that promote growth and stress resistance.</p>
2023-12-15 | MTBLS8903 | MetaboLights
Project description:Glioblastoma (GBM) is the most common type of primary brain tumor. Patients with GBM have poor survival outcomes. Isolated components of Momordica charantia have anticancer effects. However, the bioactivity of M. charantia extracts against GBM remains unknown. We tested four major extracts of M. charantia and found that momordicine I reduced glioma cell viability without serious cytotoxic effects on astrocytes. Momordicine I suppressed glioma cell colony formation, proliferation, migration, and invasion. Momordicine I also induced apoptosis, intracellular reactive oxygen species (ROS) production, and senescence in glioma cells. Moreover, momordicine I decreased the oxidative phosphorylation capacity of glioma cells and inhibited tumor sphere formation in temozolomide (TMZ)-resistant GBM cells. We further explored whether the antiglioma effect of momordicine I may be related to cell cycle modulation and DLGPA5 expression. Our results indicate that the cytotoxic effect of momordicine I on glioma cells suggests its potential therapeutic application to GBM treatment. See also Figure 1(Fig. 1).
| S-EPMC10391611 | biostudies-literature