Targeting Ketone Body Metabolism in Mitigating Gemcitabine Resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1176263 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31076451_1.fastq.gz | Fastqsanger.gz | |||
| SRR31076451_2.fastq.gz | Fastqsanger.gz | |||
| SRR31076452_1.fastq.gz | Fastqsanger.gz | |||
| SRR31076452_2.fastq.gz | Fastqsanger.gz | |||
| SRR31076453_1.fastq.gz | Fastqsanger.gz |
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Project description:Chemotherapy is often combined with surgery for muscle invasive and non-muscle invasive bladder cancer. However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism which promotes cancer reprogramming via the metabolic enzyme, OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in chemo-resistant bladder cancer patients. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant bladder cancer, knocking out OXCT1 restored gemcitabine sensitivity, and administering the non-metabolizable βHB, enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extra-metabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor, OVOL1, as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a chemotherapy-treated BCa patient cohort. The knockout of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of bladder cancer supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.
2025-01-02 | GSE280095 | GEO
Project description:Chemotherapy is often combined with surgery for muscle invasive and nonmuscle invasive bladder cancer (BCa). However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism that promotes cancer reprogramming via the metabolic enzyme OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in patients with chemoresistant BCa. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant BCa, knocking out OXCT1 restored gemcitabine sensitivity, and administering the nonmetabolizable βHB enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extrametabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor OVOL1 as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a cohort of patients with BCa who have been treated with chemotherapy. The KO of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of BCa supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.
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Project description:Diets characterized by increased blood levels of ketone bodies can protect the brain against a variety of acute and chronic neurological diseases. Moreover, ketone bodies are neuroprotective in many in vitro models of neurological injury. The underlying mechanisms remain unknown however. Recently, we have shown that ketone bodies do not only decrease neuronal injury and death but also protect long-term potentiation in acute hippocampal slices exposed to oxidative stress in the form of exogenous hydrogen peroxide. Elucidating the mechanisms behind the effects of ketone bodies on neuronal survival and function will undoubtedly lead to the development of novel neuroprotective treatments. Our aim is to determine acute changes in gene expression of CA1 pyramidal neurons exposed to various duration of the ketone bodies acetoacetate and beta-hydroxybutyrate. CA1 hippocampal pyramidal neurons exposed to oxidative stress do not display any long-term potention following burst stimulation of Schaffer collaterals. Incubation with the ketone bodies acetoacetate and beta-hydroxybutyrate for at least 20 min prior to hydrogen peroxide application restores long-term potentiation to control levels. We hypothesize that the neuroprotective effects of ketone bodies are mediated by changes in gene expression. Acute hippocampal slices (400 microns in thickness) were obtained from 4 week-old rats and exposed to acetoacetate and beta-hydroxybutyrate (1 mM each) for 1 h and 6 h. A control group was incubated in artificial cerebrospinal fluid only. After treatment, the hippocampal slices were used immediately for RNA isolation. Isolated RNA was sent for analysis. Each sample sent for analysis included tissue from 7 separate animals. Hybridization to an Affymetrix array is being performed 3 times for each experimental condition.
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Project description:It is well established that EZH2, a lysine methyltransferase, is upregulated in most of aggressive cancers, highlighting the importance of EZH2 in cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including cancer. Despite this, evidence of EZH2's role in regulating cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belongs to the HMG-CoA synthase, in prostate and breast cancers. Furthermore, HMGCS2 is inversely related to cancer progression and prognosis in these cancers and is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate cancer progression by targeting EZH2 via direct protein-compound interaction -mediated protein degradation. More importantly, ketone drink of BHB administration dramatically reduces tumor size and weight in a prostate cancer xenograft model. Combining ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, EZH2- HMGCS2-BHB regulatory network plays a critical role in the progression of prostate cancer and ketone drink is a novel therapeutic tool for patients with aggressive prostate cancer.
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Project description:Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic cancer patients. In recent years, technical advances have developed experimental methods that unveiled a high degree of inter- and intratumoral heterogeneity in pancreatic cancer. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Experimental Design: We addressed the effect of ITH on response to gemcitabine treatment using single cell-derived cell lines (SCDCL) from the classical-like cell line BxPC3 and the basal-like cell line Panc-1 which were analyzed by mRNA-seq and mass spectrometry. Results: Individual SCDCLs of the parental tumor cell populations of BxPC3 and Panc-1 showed considerable heterogeneity in response to gemcitabine. Unsupervised principal component analysis (PCA) including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this clustering was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance to gemcitabine. Feature extraction of proteomes again identified less proteins whose expression was associated with the response of individual SCDCLs in Panc-1 compared to BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusions: Our model system of SCDCLs identified gemcitabine-resistant subclones within a parental tumor population and provides evidence for the critical role of ITH for treatment response in pancreatic cancer. Through molecular profiling, we identified specific signaling pathways and protein signatures that might help to explain the differential response to treatment among clones. We exploited these molecular differences for an improved and more targeted therapy of resistant subclones of a heterogeneous tumor.
2023-09-19 | PXD042256 | Pride
Project description:It is well established that EZH2, a lysine methyltransferase, is upregulated in most of aggressive cancers, highlighting the importance of EZH2 in cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including cancer. Despite this, evidence of EZH2's role in regulating cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belongs to the HMG-CoA synthase, in prostate and breast cancers. Furthermore, HMGCS2 is inversely related to cancer progression and prognosis in these cancers and is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate cancer progression by targeting EZH2 via direct protein-compound interaction -mediated protein degradation. More importantly, ketone drink of BHB administration dramatically reduces tumor size and weight in a prostate cancer xenograft model. Combining ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, EZH2- HMGCS2-BHB regulatory network plays a critical role in the progression of prostate cancer and ketone drink is a novel therapeutic tool for patients with aggressive prostate cancer.
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