Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis
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ABSTRACT:
PROVIDER: PRJNA864053 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-07-20 | GSE210156 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. The diversity and composition of intra-tumoral microbiota are associated with PDAC outcomes, and modulating the tumor microbiota has the potential to influence tumor growth and host-immune response. Here, we explore whether intervention with butyrate-producing probiotic can limit PDAC progression. By analyzing TCGA (PAAD) dataset, we found that tumoral butyrate-producing microbiota links to better prognosis and less aggressive features of PDAC. Intervention with Clostridium butyricum or its metabolite butyrate triggered superoxidative stress and intracellular lipid accumulation, which enhanced ferroptosis susceptibility of PDAC. Our study reveals a novel antitumor mechanism of butyrate, and suggests the therapeutic potential of butyrate-producing probiotics in PDAC.
2025-03-15 | GSE227418 | GEO
Project description:Intracellular calcium signaling is critical for initiating and sustaining diverse cellular functions including transcription, synaptic signaling, muscle contraction, apoptosis and fertilization. Trans-membrane 203 (TMEM203) was identified here in cDNA overexpression screens for proteins capable of modulating intracellular calcium levels using activation of a calcium/calcineurin regulated transcription factor as an indicator. Overexpression of TMEM203 resulted in a reduction of Endoplasmic Reticulum (ER) calcium stores and elevation in basal cytoplasmic calcium levels. TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux. Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis. Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation. Expression profiling studies showed significant alternations in expression of calcium channels and pumps in testes and concurrently Tmem203 deficient spermatocytes demonstrated significantly altered calcium handling. Thus Tmem203 is an evolutionarily conserved regulator of cellular calcium homeostasis, is required for spermatogenesis and provides a causal link between intracellular calcium regulation and spermiogenesis. Testes were harvested from control and Tmem203 null mice at 24 weeks of age. 4 wild type testes and 5 null mice testes were probed using Affymetrix Mouse Genome 430 2.0 platform.
2015-04-15 | E-GEOD-66791 | biostudies-arrayexpress
Project description:Intracellular calcium signaling is critical for initiating and sustaining diverse cellular functions including transcription, synaptic signaling, muscle contraction, apoptosis and fertilization. Trans-membrane 203 (TMEM203) was identified here in cDNA overexpression screens for proteins capable of modulating intracellular calcium levels using activation of a calcium/calcineurin regulated transcription factor as an indicator. Overexpression of TMEM203 resulted in a reduction of Endoplasmic Reticulum (ER) calcium stores and elevation in basal cytoplasmic calcium levels. TMEM203 protein was localized to the ER and found associated with a number of ER proteins which regulate ER calcium entry and efflux. Mouse Embryonic Fibroblasts (MEFs) derived from Tmem203 deficient mice had reduced ER calcium stores and altered calcium homeostasis. Tmem203 deficient mice were viable though male knockout mice were infertile and exhibited a severe block in spermiogenesis and spermiation. Expression profiling studies showed significant alternations in expression of calcium channels and pumps in testes and concurrently Tmem203 deficient spermatocytes demonstrated significantly altered calcium handling. Thus Tmem203 is an evolutionarily conserved regulator of cellular calcium homeostasis, is required for spermatogenesis and provides a causal link between intracellular calcium regulation and spermiogenesis.
2015-04-15 | GSE66791 | GEO
Project description:To further elucidate the mechanism of butyrate mediated chemoprevention of colorectal cancer,we have employed whole genome microarray expression profiling as a discovery platform to identify genes that differentially expressed in mice from Butyrate group compared those from DMH group. The mice of DMH group were received normal diet (calcium concentration,1.24%) and subcutaneous injection of 1,2-Dimethylhydrazine at a dose of 20 mg/kg once weekly for 20 weeks; the mice of Butyrate group were received high calcium diet (calcium concentration,3%) with 1.5% Butyrate and subcutaneous injection of 1,2-Dimethylhydrazine at a dose of 20 mg/kg once weekly for 20 weeks. The mice were sarcrificed at 24 week. Nine normal colonic mucosa (3 from DMH group, 3 from Butyrate group mice with tumors, and 3 from Butyrate group mice without tumors) were used for the microarray analysis. The differentially expressed genes were identified between butyrate group and DMH group,as long as differentially expressed pathways and gene ontology terms.
2011-12-31 | E-GEOD-25858 | biostudies-arrayexpress
Project description:The balance between tolerogenic and inflammatory responses determines immune homeostasis in the gut. Dysbiosis and a defective host defense against invading intestinal bacteria can shift this balance via bacterial-derived metabolites and trigger chronic inflammation. We show that the short chain fatty acid butyrate modulates monocyte to macrophage differentiation by promoting antimicrobial effector functions. The presence of butyrate modulates antimicrobial activity via a shift in macrophage metabolism and reduction in mTOR activity. This mechanism is furthermore dependent on the inhibitory function of butyrate on histone deacetylase 3 (HDAC3) driving transcription of a set of antimicrobial peptides including calprotectin. The increased antimicrobial activity against several bacterial species is not associated with increased production of conventional cytokines. Butyrate imprints antimicrobial activity of intestinal macrophages in vivo. Our data suggest that commensal bacteria derived butyrate stabilize gut homeostasis by promoting antimicrobial host defense pathways in monocytes that differentiate into intestinal macrophages.
2019-01-30 | GSE111049 | GEO
Project description:To further elucidate the mechanism of butyrate mediated chemoprevention of colorectal cancer,we have employed whole genome microarray expression profiling as a discovery platform to identify genes that differentially expressed in mice from Butyrate group compared those from DMH group. The mice of DMH group were received normal diet (calcium concentration,1.24%) and subcutaneous injection of 1,2-Dimethylhydrazine at a dose of 20 mg/kg once weekly for 20 weeks; the mice of Butyrate group were received high calcium diet (calcium concentration,3%) with 1.5% Butyrate and subcutaneous injection of 1,2-Dimethylhydrazine at a dose of 20 mg/kg once weekly for 20 weeks. The mice were sarcrificed at 24 week. Nine normal colonic mucosa (3 from DMH group, 3 from Butyrate group mice with tumors, and 3 from Butyrate group mice without tumors) were used for the microarray analysis.
2011-12-31 | GSE25858 | GEO
Project description:The commensal-derived metabolite butyrate imprints an antimicrobial program in macrophages
| PRJNA435719 | ENA
Project description:Metabolite accumulation has pleiotropic, including toxic, effects on cellular physiology, but such effects are not well understood at the genomic level. Using DNA microarrays, the Clostridium acetobutylicum transcriptional stress response to butyrate was analyzed. Keywords: stress response
2007-12-29 | GSE4992 | GEO
Project description:ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), the phase 3 morbidity and mortality trial of torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, identified previously undescribed changes in plasma levels of potassium, sodium, bicarbonate, and aldosterone. A key question after this trial is whether the failure of torcetrapib was a result of CETP inhibition or of some other pharmacology of the molecule. The direct effects of torcetrapib and related molecules on adrenal steroid production were assessed in cell culture using the H295R as well as the newly developed HAC15 human adrenal carcinoma cell lines. Torcetrapib induced the synthesis of both aldosterone and cortisol in these two in vitro cell systems. Analysis of steroidogenic gene expression indicated that torcetrapib significantly induced the expression of CYP11B2 and CYP11B1, two enzymes in the last step of aldosterone and cortisol biosynthesis pathway, respectively. Transcription profiling indicated that torcetrapib and angiotensin II share overlapping pathways in regulating adrenal steroid biosynthesis. Hormone-induced steroid production is mainly mediated by two messengers, calcium and cAMP. An increase of intracellular calcium was observed after torcetrapib treatment, whereas cAMP was unchanged. Consistent with intracellular calcium being the key mediator of torcetrapib’s effect in adrenal cells, calcium channel blockers completely blocked torcetrapib-induced corticoid release and calcium increase. A series of compounds structurally related to torcetrapib as well as structurally distinct compounds were profiled. The results indicate that the pressor and adrenal effects observed with torcetrapib and related molecules are independent of CETP inhibition.
2009-05-02 | GSE15918 | GEO