Reprogrammed Lipid Metabolism in Bladder Cancer with Cisplatin Resistance
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Cultured Cells
DISEASE(S): Cancer
PROVIDER: ST001120 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:Due to its tendency to recur and acquire chemoresistance quickly, bladder cancer (BC) remains to be an elusive and difficult disease. Patients with recurrent and chemoresistant BC have an extremely poor prognosis. One possible approach that may provide insightful and valuable information regarding resistance mechanisms is looking into the lipid metabolism of BC cells. Metabolism of lipids is essential for cancer cells and is associated with the regulation of a variety of key cellular processes and functions. This study conducted a comparative lipidomic profiling of two isogenic human T24 bladder cancer cell lines, one of which is clinically characterized as cisplatin-sensitive (T24S) and the other as cisplatin-resistant (T24R). Immunohistochemistry analysis revealed that expression of cytosolic acetyl-CoA synthetase 2 (ACSS2) is positively correlated with aggressive BC. Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) analysis profiled a total of 1,864 lipids and levels of differentially expressed lipids suspected of being associated with cisplatin resistance were determined. In addition, we found that ACSS2 inhibition greatly perturbed levels of metabolites, including CE(18:1), CE(22:6), TG(49:1), and TG(53:2). This study broadens our current knowledge on the links between cisplatin resistance and lipid metabolism in aggressive BC and suggests potential biomarkers for identifying higher-risk patients.
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Project description:We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.
| S-EPMC7469822 | biostudies-literature
Project description:PurposeThe overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity.ResultsSignificant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1).ConclusionsOur study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.
| S-EPMC8819945 | biostudies-literature
Project description:Metabolism vulnerability of cisplatin resistance in BCa cells remains to be discovered, which we applied integrated multi-omics analysis to elucidate the metabolism related regulation mechanism in bladder cancer (BCa) microenvironment. Integrated multi-omics analysis of metabolomics and proteomics revealed that MAT2A regulated methionine metabolism contributes to cisplatin resistance in BCa cells. We further validated MAT2A and cancer stem cell markers were up-regulated and circARHGAP10 was down-regulated through the regulation of MAT2A protein stability in cisplatin resistant BCa cells. circARHGAP10 formed a complex with MAT2A and TRIM25 to accelerate the degradation of MAT2A through ubiquitin-proteasome pathway. Knockdown of MAT2A through overexpression of circARHGAP10 and restriction of methionine up-take was sufficient to overcome cisplatin resistance in vivo in immuno-deficiency model but not in immuno-competent model. Tumor-infiltrating CD8+ T cells characterized an exhausted phenotype in tumors with low methionine. High expression of SLC7A6 in BCa negatively correlated with expression of CD8. Synergistic inhibition of MAT2A and SLC7A6 could overcome cisplatin resistance in immuno-competent model in vivo. Cisplatin resistant BCa cells rely on methionine for survival and stem cell renewal. circARHGAP10/TRIM25/MAT2A regulation pathway plays an important role in cisplatin resistant BCa cells while circARHGAP10 and SLC7A6 should be evaluated as one of the therapeutic target of cisplatin resistant BCa.
| S-EPMC10427658 | biostudies-literature
Project description:Chemotherapy resistance is traditionally attributed to DNA mutations that confer a survival advantage under drug selection pressure. However, in bladder cancer and other malignancies, we and others have previously reported that cancer cells can convert spontaneously to an aggressive drug-resistant phenotype without prior drug selection or mutational events. In the current work, we explored possible epigenetic mechanisms behind this phenotypic plasticity. Using Hoechst dye exclusion and flow cytometry, we isolated the aggressive drug-resistant cells and analyzed their chromatin accessibility at regulatory elements. Compared to the rest of the cancer cell population, the aggressive drug-resistant cells exhibited enhancer accessibility changes. In particular, we found that differentially accessible enhancers were enriched for the FOXC1 transcription factor motif, and that FOXC1 was the most significantly overexpressed gene in aggressive drug-resistant cells. ChIP-seq analysis revealed that differentially accessible enhancers in aggressive drug-resistant cells had a higher FOXC1 binding, which regulated the expression of adjacent cancer-relevant genes like ABCB1 and ID3. Accordingly, cisplatin treatment of bladder cancer cells led to an increased FOXC1 expression, which mediated cell survival and conversion to a drug-resistant phenotype. Collectively, these findings suggest that FOXC1 contributes to phenotypic plasticity by binding enhancers and promoting a mutation-independent shift towards cisplatin resistance in bladder cancer.
| S-EPMC8996937 | biostudies-literature
Project description:Autophagy-dependent cisplatin resistance poses a challenge in bladder cancer treatment. SIRT1, a protein deacetylase, is involved in autophagy regulation. However, the precise mechanism through which SIRT1 mediates cisplatin resistance in bladder cancer via autophagy remains unclear. In this study, we developed a cisplatin-resistant T24/DDP cell line to investigate this mechanism. The apoptosis rate and cell viability were assessed using flow cytometry and the CCK8 method. The expression levels of the relevant RNA and protein were determined using RT-qPCR and a Western blot analysis, respectively. Immunoprecipitation was utilized to validate the interaction between SIRT1 and Beclin1, as well as to determine the acetylation level of Beclin1. The findings indicated the successful construction of the T24/DDP cell line, which exhibited autophagy-dependent cisplatin resistance. Inhibiting autophagy significantly reduced the drug resistance index of these cells. The T24/DDP cell line showed a high SIRT1 expression level. The overexpression of SIRT1 activated autophagy, thereby further promoting cisplatin resistance in the T24/DDP cell line. Conversely, inhibiting autophagy counteracted the cisplatin-resistance-promoting effects of SIRT1. Silencing SIRT1 led to increased acetylation of Beclin1, the inhibition of autophagy, and a reduction in the cisplatin resistance of the T24/DDP cell line. Introducing a double mutation (lysine 430 and 437 to arginine, 2KR) in Beclin-1 inhibited acetylation and activated autophagy, effectively reversing the decreased cisplatin resistance resulting from SIRT1 silencing. In summary, our study elucidated that SIRT1 promotes cisplatin resistance in human bladder cancer T24 cells through Beclin1-deacetylation-mediated autophagy activation. These findings suggest a potential new strategy for reversing cisplatin resistance in bladder cancer.
| S-EPMC10778480 | biostudies-literature
Project description:BackgroundCisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa.MethodsCircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity.ResultsWe identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors.ConclusionThese studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.
| S-EPMC10759346 | biostudies-literature
Project description:In this study, we identified microRNAs (miRNAs) involved in cisplatin (CDDP) resistance in bladder cancer (BCa). After establishing CDDP-resistant BCa cell lines (T24RC and EJ138RC), TaqMan arrays revealed that members of the miR-200 family (miR-200b, miR-200a and miR-429) were downregulated in T24RC as compared to parental T24 cells. miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2'-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2'-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. These results suggest downregulation of miR-200b is associated with CDDP resistance in BCa. Epigenetic silencing of miR-200b may be a marker of CDDP resistance and a useful therapeutic target for overcoming CDDP resistance in BCa.
| S-EPMC5966259 | biostudies-literature
Project description:Cisplatin (CDDP) remains a key drug for patients with advanced bladder cancer (BC), despite the emergence of new therapeutic agents; thus, the identification of factors contributing to CDDP treatment resistance is crucial. As acidity of the tumor microenvironment has been reported to be associated with treatment resistance and poor prognosis across various cancer types, our objectives in this study were to investigate the effects of an acidic environment on BC cells and elucidate the mechanisms behind CDDP resistance. Our findings show that BC cells cultured under acidic conditions developed cisplatin resistance as acidity increased. Notably, CDDP administered to BC cells in a pH 6.0 environment required double the concentration, compared to those in a pH 7.5 environment, to achieve equivalent toxicity. Using chloroquine and navitoclax, we identified the involvement of the Bcl-2 and LC3B pathways in the acquisition of CDDP resistance under acidic conditions. A Western blot analysis revealed that the activations of Bcl-2 and XIAP expression appear to inhibit both apoptotic and autophagic cell death. Taken together, these results suggest that alleviating the acidity of the tumor microenvironment in clinical settings might enhance BC sensitivity to CDDP.
| S-EPMC11763506 | biostudies-literature
Project description:BackgroundBladder cancer is one of the most common malignancies of the urinary system with an unfavorable prognosis. More and more studies have suggested that lipid metabolism could influence the progression and treatment of tumors. However, there are few studies exploring the relationship between lipid metabolism and bladder cancer. This study aimed to explore the roles that lipid metabolism-related genes play in patients with bladder cancer.MethodsTCGA_BLCA cohort and GSE13507 cohort were included in this study, and transcriptional and somatic mutation profiles of 309 lipid metabolism-related genes were analyzed to discover the critical lipid metabolism-related genes in the incurrence and progression of bladder cancer. Furthermore, the TCGA_BLCA cohort was randomly divided into training set and validation set, and the GSE13507 cohort was served as an external independent validation set. We performed the LASSO regression and multivariate Cox regression in training set to develop a prognostic signature and further verified this signature in TCGA_BLCA validation set and GSE13507 external validation set. Finally, we systematically investigated the association between this signature and tumor microenvironment, drug response, and potential functions and then verified the differential expression status of signature genes in the protein level by immunohistochemistry.ResultsA novel 6-lipidmetabolism-related gene signature was identified and validated, and this risk score model could predict the prognosis of patients with bladder cancer. In addition, the prognostic model was tightly related to immune cell infiltration and tumor mutation burden. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) showed that mTOR signaling pathway, G2M checkpoint, fatty acid metabolism, and hypoxia were enriched in patients in the high-risk score groups. Furthermore, 3 therapies specific for bladder cancer patients in different risk scores were identified.Conclusions. In conclusion, we investigated the lipid metabolism-related genes in bladder cancer through comprehensive bioinformatic analysis. A novel 6-gene signature associated with lipid metabolism for predicting the outcomes of patients with bladder cancer was conducted and validated. Furthermore, the risk score model could be utilized to indicate the choice of therapy in bladder cancer.
| S-EPMC9484922 | biostudies-literature