Transcriptional changes in B cells induced by MCT1 depletion
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PROVIDER: PRJNA1036617 | ENA |
REPOSITORIES: ENA
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Project description:Using RNA-seq we identified the gene expression changes in MCT1-deficient B cells.
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Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.
2016-03-08 | E-GEOD-76675 | biostudies-arrayexpress
Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics.
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Project description:Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1f/fMb1Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.
2023-12-14 | PXD047325 | Pride
Project description:Adipose tissue is an active producer of lactate. In obesity, the increased size of adipocytes is accompanied by an increase in lactate production in adipose tissue, caused by hypoxia in obese adipocytes. How lactate affects metabolism in adipocyte and insulin sensitivity remains unclear. Here we develop a mouse model of MCT1,coding by Slc16a1, specific deletion in adipose tissues, using the AP2 promoter to drive Cre expression. This MCT1 AKO mice develop more severe insulin resistance in obesity with 16 weeks high fat diet treatment, while few changes happen to lipid metabolism in adipose tissues. We used RNA-seq to analyze the gene expression patterns of eWAT of obese MCT1 AKO mice compared to WT, and found significant changes in innate immune signaling and adipocyte apoptosis that reflect systemic inflammation and insulin resistance.
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