Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis

ABSTRACT: Gut microbiota are recognized to be important for anticancer therapy, yet the underlying mechanism is not clear. Herein, we demonstrate that gut microbial metabolite butyrate improves anticancer therapy efficacy by regulating intracellular calcium homeostasis. Butyrate metabolism is activated in hepatocellular carcinoma (HCC) patients. Butyrate supplementation or depletion of short-chain Acyl-CoA dehydrogenase (ACADS), a key enzyme for butyrate metabolism, significantly inhibit HCC proliferation and metastasis. Profiling analysis of genes upregulated by butyrate supplementation or ACADS knockdown reveal that calcium signaling pathway is activated, leading to dysregulation of intracellular calcium homeostasis and production of reactive oxygen species (ROS). Butyrate supplementation improves the therapy efficacy of a tyrosine kinase inhibitor sorafenib. Butyrate and sorafenib co-encapsulated monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide)-poly(L-lysine)-glypican 3 (PEAL-GPC3) nanoparticles significantly reduce HCC progression. Our findings provide new insight into the mechanisms that the gut microbial metabolites inhibit HCC progression and suggest a translatable therapeutics approach to enhance the clinical targeted therapeutic efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210156 | GEO | 2025/07/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Fasting reverses drug-resistance in hepatocellular carcinoma through p53-dependent metabolic synergism

Project description:Cancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitise resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically as inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR-signalling, prevents this Warburg shift. p53 is necessary and sufficient for the sorafenib-sensitizing effect of nutrient restriction and crucial for improvement of sorafenib efficacy through intermittent fasting (IF) in an orthotopic HCC mouse model. Together, our data indicate IF and sorafenib as clinically actionable, rational combination therapy for HCC with intact p53 signalling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies with the goal of improving therapy response in advanced-stage, and possibly even early-stage, HCC.

2022-02-16 | PXD022723 | Pride

Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis

Project description:Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis

| PRJNA864053 | ENA

Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergizes the anticancer effects of sorafenib in hepatocellular carcinoma

Project description:Sorafenib, a multiple-kinase inhibitor, has been widely used as a first-line anticancer drug for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance to sorafenib is frequently observed in clinical applications. Potential non-kinase targets of sorafenib have not been well documented and may provide insights into reversing drug resistance. Herein, we report that sorafenib exerted its anticancer effects by activating metallothionein 1G (MT1G) expression. MT1G served as a novel marker in HCC and correlated well with patient survival. MT1G overexpression suppressed the cellular proliferation, migration, invasion, and tumor formation of HCC, and sensitized cells to sorafenib treatment. However, the disruption of MT1G attenuated sorafenib’s anticancer effects. Mechanistically, sorafenib upregulated MT1G expression via hypomethylation of its promoter region by binding and inhibiting DNA methyltransferase 1 (DNMT1) and increasing its promoter accessibility in HCC cells. The activation of MT1G also inhibited CA9 transcription through the degradation of HIF1a as mediated by KLF4. Our collective data revealed that sorafenib exerted its anticancer effects through epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis in HCC, and that the activation of MT1G might constitute a strategy for reversing sorafenib resistance.

2022-04-30 | GSE192771 | GEO

Carbonic anhydrase 2 facilitates sorafenib resistance by counteracting MCT4-mediated intracellular pH dysregulation in hepatocellular carcinoma

Project description:Sorafenib, the first targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics over a decade. However, its effectiveness is severely hindered by the acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that carbonic anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pHi) by suppressing monocarboxylate transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pHi dysregulation upon sorafenib treatment, maintaining pHi homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both in vitro and in vivo. Importantly, analysis of clinical samples demonstrates a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.

2024-10-24 | PXD056884 | Pride

Mannose enhances anti-PD-1 therapy efficacy in ovarian cancer via modulating gut microbial metabolite.

Project description:The gut microbiome serves as a crucial mediator for improving the efficacy of immune checkpoint blockade (ICB) therapy. Here, we show that oral supplementation with prebiotics (mannose) retarded tumor growth in immunocompetent mice in a gut microbiota dependent manner, correlating with the enrichment of Faecalibaculum. Mannose generates an immune-stimulatory tumor microenvironment (TME) characterized by an increase percentage of effector and memory CD8+T cells, accompanied by a prominent immunoreactivegeneexpressionsignature. Most importantly, mannose modulates the stemness program of CD8+T cells and facilitates the generation of progenitor exhausted CD8+T cells (Tpex). Mechanistically, mannose increases gut microbial production of the short-chain fatty acids (SCFA) propionate and butyrate. Administration of propionate and butyrate suppresses tumor progression and stimulates the expansion and differentiation of Tpex both in vivo and in vitro. Mannose synergized with PD-1 blockade in tumor regression and augmented intratumoral Tpex differentiation into intermediate exhausted CD8+T cells (Tex-int) and terminally exhausted CD8+T cells (Tex-term). Moreover, we identified a mannose-therapy related gene signature associated with favorable responses to ICB in pan-cancer. Overall, our findings support the rationale for combining dietary supplementation of mannose with anti-PD-1 immunotherapy in ovarian cancer, and its clinical translation.

2025-03-17 | GSE271477 | GEO

In vivo screen identifies LXR agonism potentiates sorafenib killing of hepatocellular carcinoma

Project description:Background & Aims: Existing drug therapies for hepatocellular carcinoma (HCC), including sorafenib, extend patient survival by only three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. Methods: We implemented an in vivo genetic screening paradigm utilizing a library of 43 genes-of-interest expressed in the context of repopulation of the injured livers of Fumarylacetoacetate Hydrolase-deficient (Fah-/-) mice, which led to highly penetrant HCC. We treated mice with vehicle or sorafenib, then determined the genetic drivers of each tumor from the library. Liver X Receptor alpha (LXRalpha) emerged as a potential target. To examine LXRalpha agonism in combination with sorafenib treatment, we added varying concentrations of sorafenib and LXRalpha agonist drugs to HCC cell lines. To elucidate the mechanism of tumor death, we performed transcriptomic analysis. Results: Fah-/- mice injected with the screening library developed HCC tumor clones containing Myc cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib-resistant HCCs that were significantly depleted in Nr1h3 cDNA, encoding LXRalpha, suggesting that LXRalpha activation is incompatible with tumor growth in the presence of sorafenib treatment in vivo. Combination treatment using sorafenib and LXR agonist drugs in multiple HCC cell lines led to enhanced cell death as compared to monotherapy, due to reduced expression of cell cycle regulators and increased expression of genes associated with apoptosis. Combination therapy also enhanced cell death in a sorafenib-resistant primary human HCC cell line. Conclusions: We have completed a novel drug resistance screen in vivo, and identified that LXR agonism potentiates the efficacy of sorafenib in treating HCC.

2020-05-29 | GSE151412 | GEO

USP29-mediated HIF1a stabilization promotes Sorafenib resistance of hepatocellular carcinoma cells by upregulating glycolysis

Project description:Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia inducible factor 1 a (HIF1a) and increased aerobic glycolysis metabolism represent drivers of the development of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1a is activated and how its activity and the subsequent induction of aerobic glycolysis promotes Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1a and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we have identified USP29 as a critical deubiquitylase (DUB) of HIF1a, which directly deubiquitinates and stabilizes HIF1a and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1a is the gene encoding for hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1a transcriptional activity, reduces the levels of aerobic glycolysis and reinstalls the sensitivity to Sorafenib treatment in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1a, USP29 promotes Sorafenib resistance in HCC cells by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

2021-07-27 | GSE158458 | GEO

RNA-seq of Ctrl and NaBu-treated CD8+ T cells in vitro

Project description:Recent studies in both mice and human have suggested that the gut microbiota could modulate tumor response to chemotherapeutic agents or immunotherapies. However, the underlying mechanism has not been well characterized. Here, we found that disruption of the intestinal microbiota with antibiotics impaired the anti-cancer efficacy of oxaliplatin, which was correlated with the reduction of lots of the intestinal microbial metabolites including butyrate, one of the short chain fatty acids. Re-supplementation of either the whole intestinal microbial metabolites or butyrate could rescue the therapeutic responses of oxaliplatin in the microbiota-destroyed tumor-bearing mice by modulating CD8+ T cell function in the tumor microenvironment. Further experiments showed butyrate boosted the anti-tumor cytotoxic CD8+ T cell responses through ID2, a key transcription regulator highly expressed by tumor-infiltrating CD8+ T cells. Butyrate induced ID2 expression in CD8+ T cells, while ID2 further promoted the proliferation and function of CD8+ T cells through IL-12 signaling. Together, our findings suggest that gut microbial metabolite butyrate could promote the anti-tumor therapeutic efficacy through the ID2-dependent regulation of CD8+ T cell immunity.

2021-03-24 | GSE115426 | GEO

RNA-seq of WT and ID2KO CD8+ T cells in iLN of tumor-bearing mice after oxaliplatin treatment

2021-03-24 | GSE115283 | GEO

Sorafenib resistance related circRNAs

Project description:Sorafenib resistance up-regulated circRNA_104797 could be transmitted by exosomes and responsible for the spread of Sorafenib resistance among HCC cells. CircRNA_104797 was critical for Sorafenib resistance maintenance and silencing circRNA_104797 could substantially increase the efficacy of Sorafenib by inducing apoptosis. Mechanism dissection unveiled that circRNA_104797 could specifically sponge miR-103a-2-5p and miR-660-3p and act as a competing endogenous RNA (ceRNA), thus competitively activated wnt/β-catenin pathway and induced Sorafenib resistance. Meanwhile, LC-MS/MS also revealed that circRNA_104797 could specifically bind to translation related proteins, which might regulate downstream glycan biosynthesis and lipid metabolism, and finally induce Sorafenib resistance. In vivo experiments portrayed a promising clinical application by locally injection of in vivo-grade siRNA for circRNA_104797 by TACE or other manners, which could intensively enhance Sorafenib efficacy in HCC patients. The clinical application of in vivo-grade siRNA for circRNA_104797 in Sorafenib treated HCC patients might shed bright future for the management of advanced HCC.

2020-07-25 | GSE101850 | GEO

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