Mevalonate pathway inhibition affects bladder cancer metastasis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE252007 | GEO | 2024/09/08
REPOSITORIES: GEO
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Project description:Metastasis is an important factor affecting the prognosis and survival of bladder cancer (BLCA) patients. Our previous study found that the mevalonate pathway is associated with the migratory ability of bladder cancer cells, but the exact mechanism is unclear. Here, we found that BLCA patients with mevalonate pathway activation had a poorer prognosis. Inhibition of the mevalonate pathway (simvastatin or zoledronic acid) resulted in a significant decrease in the migratory ability of BLCA cells. Therefore, we used proteomics to detect simvastatin- or zoledronic acid-treated BLCA cells to explore the effect of the mevalonate pathway on key proteins in BLCA cells.
2024-09-09 | PXD048067 |
Project description:Simvastatin has been widely used for treatment of hypercholesterolemia due to its ability to inhibit HMG-CoA reductase, the rate limiting enzyme of de novo cholesterol synthesis via mevalonate pathway. Its inhibitory action causes also depletion of pathway intermediates, farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), which are inevitable for proper targeting of small GTPases (e.g. Ras proteins) to their site of action. We profiled by array the gene expression of MIA PaCa-2 cells treated with simvastatin, FPP, GGPP and their combinations. The inhibitory effect of statins on GFP-K-Ras protein trafficking were partially prevented by addition of the mevalonate pathway intermediates. We conclude that the anticancer effect of simvastatin is to a large extent mediated through isoprenoid intermediates of the mevalonate pathway.
2018-03-31 | E-MTAB-3263 | biostudies-arrayexpress
Project description:This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMGCR inhibitors, specifically simvastatin, are significantly associated with a reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several associated pathways. Higher levels of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and VLDL cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA. Meanwhile, RhoB is a key protein involved in the regulation of bladder cancer cell metastasis by simvastatin. Therefore, we tested the changes of key genes in bladder cancer cells after simvastatin (HMGCR inhibitor) treatment and overexpression of RhoB, respectively, using RNA sequencing.
2024-09-08 | GSE270394 | GEO
Project description:Paretal KM12 and NTRK inhibitor resistant cells established from KM12 in our laboratory was compared to search for and analyze significant factors related to resistance mechanism. To investigated the mechanism of resistance to NTRK-TKI, we establish resistant cells to three type NTRK-TKIs (Larotrectinib, Entrectinib and Selitrectinib) by step -wise methods using KM12 with TPM5-NTRK1 rearrangement for 6 months. (KM12-LR, KM12-ER and KM12-SR) 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) over expression was observed commonly in three resistance cells. Lower expression of SREBP2 and PPARα in two cells (KM12-ER and KM12-SR) in which HMGCS2 was more overexpressed than parental KM12 and KM12-LR. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved NTRK-TKIs sensitivity, but further treatment with mevalonolactone after knockdown HMGCS2 reintroduced NTRK-TKIs resistance. In addition, simvastatin and silibinin had synergic effect with NTRK-TKIs to resistant cells and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin against KM12. These results suggested that HMGCS2 overexpression induces resistance to NTRK-TKI via the mevalonate pathway. In addition, statin inhibited mevalonate pathway may be useful for overcoming this mechanism resistance.
2023-03-10 | GSE225681 | GEO
Project description:Microarray gene expression profiling reveals that simvastatin regulates the expression of M phase cell cycle genes and mevalonate metabolism
2023-05-01 | GSE215949 | GEO
Project description:Acetyl-CoA acetyltransferase 1 (ACAT1) played a key role in regulating gene expression and tumorigenesis. Nevertheless, the biological function of ACAT1 in bladder cancer (BLCA) has yet to be elucidated. This study aimed to elucidate the bioinformatics features and biological functions of ACAT1 in BLCA. Here, we demonstrate for the first time that ACAT1 is elevated in BLCA tissues, correlating with specific clinicopathological features and an unfavorable prognosis for survival in BLCA patients. ACAT1 emerged as an independent risk factor in BLCA. Phenotypically, ACAT1 knockdown inhibited the proliferation and migration of BLCA cells both in vivo and in vitro, whereas ACAT1 overexpression yielded the opposite phenotype. Mechanistically, ACAT1 enhances BLCA cells proliferation by activating cell cycle through AKT/GSK3β/c-Myc signaling pathway. In conclusion, this study identifies ACAT1 as an oncogene in BLCA, demonstrating its capability to promote proliferation and metastasis of BLCA. This suggests that ACAT1 may serve as a potential molecular target for the diagnosis and treatment of BLCA.
2024-06-12 | GSE248825 | GEO
Project description:Farnesyl diphosphate synthase (FDPS), an essencial enzyme involved in mevalonate pathway, is implicated in cancers and osteoporosis by catalyzing head to tail condensation of two molecules of isopentenyl pyrophosphate with dimethylallyl pyrophosphate to form farnesyl pyrophosphate. It has also been identified as an RNA-binding protein (RBP). However, it’s exactly RNA-binding function in diseases, up to now, remain unknown. In the present study, the function of FDPS in HeLa cells was investigated with FDPS overexpression. The results showed that FDPS overexpression promoted proliferation in HeLa cells. FDPS overexpression extensively regulated the expression of genes in cell proliferation, cytokine-mediated signaling pathway, and extracellular matrix organization. In addition, FDPS extensively regulated the alternative splicing of numbers of genes related with osteoporosis, including NAB1, FGFR3, and ALPL, and FDPS-regulated DEGs and ASEs were highly validated by RT-qPCR. This is the first study to investigate the properties of FDPS as an RBP from a genome-wide perspective, our results suggested that FDPS acts as an RBP playing an important role in cancer progression and osteoporosis by altering gene expression and regulating alternative splicing, which contributes to a precise understanding of potentially FDPS-targeted therapies.
2023-02-06 | GSE151605 | GEO
Project description:Isoprenoids are a class of ubiquitous organic molecules synthesized from the five-carbon starter unit isopentenyl pyrophosphate (IPP). Comprising more than 30,000 known natural products, isoprenoids serve various important biological functions in many organisms. In bacteria, undecaprenyl pyrophosphate is absolutely required for the formation of cell wall peptidoglycan and other cell surface structures, while ubiquinones and menaquinones, both containing an essential prenyl moiety, are key electron carriers in respiratory energy generation. There is scant knowledge on the nature and regulation of bacterial isoprenoid pathways. In order to explore the cellular responses to perturbations in the mevalonate pathway, responsible for producing the isoprenoid precursor IPP in many Gram-positive bacteria and eukaryotes, we constructed three strains of Staphylococcus aureus in which each of the mevalonate pathway genes is regulated by an IPTG inducible promoter. We used DNA microarrays to profile the transcriptional effects of downregulating the components of the mevalonate pathway in S. aureus and demonstrate that decreased expression of the mevalonate pathway leads to widespread downregulation of primary metabolism genes, an upregulation in virulence factors and cell wall biosynthetic determinants, and surprisingly little compensatory expression in other isoprenoid biosynthetic genes. We subsequently correlate these transcriptional changes with downstream metabolic consequences. We used microarrays to profile the transcriptional changes incurred when downregulating mvaS, mvaA, or mvaK in S. aureus. Keywords: stress response S. aureus mutants were generated in which mvaS, mvaA, or mvaK were placed under control of the IPTG-inducible Pspac promoter. These mutants, as well as wildtype RN4220 S. aureus, were grown with or without 1 mM IPTG, harvested in exponential phase, and their total RNA was extracted and hybridized to Affymetrix GeneChips. Experiments were done in triplicate.
2010-05-05 | E-GEOD-13424 | biostudies-arrayexpress
Project description:We have discovered that loss of wild-type p53 correlates with elevated expression of mevalonate pathway genes in murine liver cancer and in human tumors. Mechanistically p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene, which inhibits SREBP-2 maturation. In mice the increase in mevalonate gene expression occurs in premalignant p53-null hepatocytes at a stage when p53 is needed to actively suppress tumorigenesis. Either RNAi mediated suppression of key genes in the mevalonate pathway or pharmacological inhibition of its rate-limiting enzyme restricts the development of mouse hepatocellular carcinomas driven by p53 loss. Conversely, like p53 loss, ablation of ABCA1 promotes tumorigenesis in a murine model and is associated with increased SREBP-2 maturation. Our findings thereby demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated tumor suppression and outline the mechanism by which this occurs.
2018-10-23 | GSE121558 | GEO
Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment
2022-10-24 | GSE216037 | GEO