Extracellular vesicles induce aggressive phenotype of luminal breast cancer cells by PKM2 phosphorylation
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ABSTRACT:
PROVIDER: PRJNA761279 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15735489_1.fastq.gz | Fastqsanger.gz | |||
| SRR15735489_2.fastq.gz | Fastqsanger.gz | |||
| SRR15735490_1.fastq.gz | Fastqsanger.gz | |||
| SRR15735490_2.fastq.gz | Fastqsanger.gz | |||
| SRR15735491_1.fastq.gz | Fastqsanger.gz |
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Project description:We report that EVs originated from cancer cells can modulate glucose metabolism in the recipient cancer cells and induce cell proliferation and aggressive phenotype. Two breast cancer cell lines with different levels of glycolytic activity, MDA-MB-231 of a claudin low-type breast cancer cell and MCF7 of luminal type breast cancer cell, were selected and co-cultured, as the originating and recipient cells using indirect co-culture system such as transwell system or microfluidic system. Proteomic profiling of the co-cultured MCF7 cells revealed proliferation and dedifferentiation of the MCF7 cells following co-culture with the MDA-MB-231 cells. Transcriptomic analysis demonstrated that glycolysis increased in the co-cultured MCF7 cells, and the component analysis of glycolysis-related genes revealed that the second-most component after cytoplasm was extracellular exosomes. In addition, 36 significant KEGG pathways were identified in a total of 856 proteins identified by proteomin analysis of MDA-MB-231-induced EVs. Among these pathways were the main pathways (glycolysis/gluconeogenesis, pyruvate metabolism, and PI3K-Akt signaling pathways) that could explain the metabolic modulation of MCF7 cells. In our work, we indirectly show that it is MDA-MB-231-derived EVs that play an important role in this phenomenon. Our study highlights the potential effects of aggressive cancer cells on other surrounding cancer cells through EVs.
2021-09-09 | GSE183551 | GEO
Project description:BackgroundAerobic glycolysis is a hallmark of glucose metabolism in cancer. Previous studies have suggested that cancer cell-derived extracellular vesicles (EVs) can modulate glucose metabolism in adjacent cells and promote disease progression. We hypothesized that EVs originating from cancer cells can modulate glucose metabolism in recipient cancer cells to induce cell proliferation and an aggressive cancer phenotype.MethodsTwo breast cancer cell lines with different levels of glycolytic activity, MDA-MB-231 cells of the claudin-low subtype and MCF7 cells of the luminal type, were selected and cocultured as the originating and recipient cells, respectively, using an indirect coculture system, such as a Transwell system or a microfluidic system. The [18F]fluorodeoxyglucose (FDG) uptake by the recipient MCF7 cells was assessed before and after coculture with MDA-MB-231 cells. Proteomic and transcriptomic analyses were performed to investigate the changes in gene expression patterns in the recipient MCF7 cells and MDA-MB-231 cell-derived EVs.ResultsFDG uptake by the recipient MCF7 cells significantly increased after coculture with MDA-MB-231 cells. In addition, phosphorylation of PKM2 at tyrosine-105 and serine-37, which is necessary for tumorigenesis and aerobic glycolysis, was highly activated in cocultured MCF7 cells. Proteomic profiling revealed the proliferation and dedifferentiation of MCF7 cells following coculture with MDA-MB-231 cells. Transcriptomic analysis demonstrated an increase in glycolysis in cocultured MCF7 cells, and the component analysis of glycolysis-related genes revealed that the second most abundant component after the cytoplasm was extracellular exosomes. In addition, proteomic analysis of EVs showed that the key proteins capable of phosphorylating PKM2 were present as cargo inside MDA-MB-231 cell-derived EVs.ConclusionsThe phenomena observed in this study suggest that cancer cells can induce a phenotype transition of other subtypes to an aggressive phenotype to consequently activate glucose metabolism via EVs. Therefore, this study could serve as a cornerstone for further research on interactions between cancer cells.
| S-EPMC8710663 | biostudies-literature
Project description:Pyruvate kinase M2 (PKM2) plays an important role in the consumption of glucose and the production of lactic acid, the striking feature of cancer metabolism. The association of PKM2 with osteosarcoma (OS) has been reported but its role in OS has not. To study this, we obtained PKM2-bound RNAs in HeLa cells. Peak calling analysis revealed that PKM2 binds to long noncoding RNAs (lncRNAs), which are associated with cancer pathogenesis and development. Validation of the PKM2-lncRNA interaction in the human OS cell line showed that lncRNA colon cancer associated transcript-1 (lncRNACCAT1) interacts with PKM2, which upregulates the phosphorylation of sterol regulatory element-binding protein 2. These factors promote the Warburg effect, lipogenesis, and OS cell growth. PKM2 seems to be a key regulator in OS by binding to lncCCAT1. This further extends the biological functions of PKM2 in tumorigenesis and makes it a novel potential therapeutic for OS.
2022-03-23 | GSE184327 | GEO
Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.
2016-03-25 | E-GEOD-79535 | biostudies-arrayexpress
Project description:Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 controls macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. These results show that TEPP-46, an activator of PKM2, reduces CD4+ T cell activation, proliferation, and cytokine production by inhibiting essential signaling pathways and preventing glycolysis.
2019-11-26 | GSE139378 | GEO
Project description:Purpose: In this study, we compared transcriptome profiling (RNA-seq) between normal mouse embryonic stem cell (E14) and Hexokinase2 (Hk2)/ Pyruvate Kinase M2 (Pkm2) overexpressed E14 cell. Result: Using an optimized data analysis workflow, we mapped over 4 billion sequence reads per sample to the mouse genome (build mm9) and identified 28698 transcripts in 5 samples. Conclusion: Our study represents the first detailed analysis of Hk2/ Pkm2 overexpressed E14 cell transcriptomes, generated by RNA-seq technology We compared transcriptome profiling (RNA-Seq) between normal mouse embryonic stem cell (E14) and E14 cells over-expressing Hexokinase2 (Hk2)/Pyruvate Kinase M2 (Pkm2)
2016-07-03 | E-GEOD-65246 | biostudies-arrayexpress
Project description:EGF is one of the most well-characterized growth factors and plays a crucial role in cell proliferation and differentiation. EGFR has been extensively explored as a therapeutic target against multiple types of cancers, such as lung cancer and glioblastoma. Recent studies have established a connection between deregulated EGF signaling and metabolic reprogramming, especially rewiring in aerobic glycolysis, which is also known as the Warburg effect and recognized as a hallmark in cancer. Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme controlling the final step of glycolysis and serves as a major regulator of the Warburg effect. We previously showed that PKM2 T405/S406 O-GlcNAcylation, a critical mark important for PKM2 detetramerization and activity, was markedly upregulated by EGF. However, the mechanism by which EGF regulates PKM2 O-GlcNAcylation still remains uncharacterized. Here we demonstrated that EGF promoted O-GlcNAc transferase (OGT) binding to PKM2 by stimulating OGT Y976 phosphorylation. As a consequence, PKM2 O-GlcNAcylation and detetramerization were upregulated, leading to a significant decrease in PKM2 activity. Moreover, other than PKM2, the association of additional phosphotyrosine binding proteins, including STAT1, STAT3, STAT5, PKCδ and p85, which are reported factors bearing O-GlcNAcylation, with OGT was also enhanced when Y976 was phosphorylated. Together, EGF-dependent Y976 phosphorylation is critical for OGT-PKM2 interaction and we propose that this post-translational modification might be important for the substrate selection by OGT.
2022-08-22 | PXD031593 | Pride
Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.
2016-03-25 | GSE79535 | GEO
Project description:Despite proven therapy options for estrogen receptor (ER)-positive tumors, a significant number of patients with these cancers exhibit relapse with associated metastasis. Studies have shown that the loss of expression of RasGAPs leads to aggressive phenotypes and poor outcomes in several cancers including breast cancer. In our study, mining TCGA gene expression profiles of ER-positive breast tumors, we found that low expression of the RasGAP, DAB2IP is associated with a significant decrease in relapse-free survival in patients with Luminal A breast tumors. Immunostaining found that DAB2IP loss occurs in grade 2 tumors and higher. Consistent with this, genes upregulated in low DAB2IP Luminal A tumors are shared with more aggressive tumor subtypes, and are associated with proliferation, metastasis, and enhanced ER-signaling. In addition, cell-based studies reveal that low DAB2IP expression in ER-positive breast cancer cells is associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the NF-B signaling pathway. Further, integrating cell-based ChIP-seq with motif analysis and TCGA RNA-seq data, we identify a candidate set of NF-B target genes that are upregulated with loss of DAB2IP and are proposed to regulate several oncogenic phenotypes, including altered RNA processing. This study provides new insight into mechanisms associated with aggressiveness and recurrence within a subset of Luminal A breast cancers that are otherwise typically less aggressive.
2024-12-18 | GSE227875 | GEO
Project description:We profiled global gene expression for two separate lines of mouse embryonic fibroblasts and find that deletion of PKM2 and expression of PKM1 does not alter global gene expression profiles. We used microarrays to futher characterize the effects of PKM1 expression compared to PKM2 expression on global gene expression in mouse embryonic fibroblasts. Primary mouse embryonic fibroblast cells were used for RNA extraction and hybridization on Affymetrix microarrays. Intensity files were RMA normalized using Affymetrix expression console.
2015-05-01 | E-GEOD-60499 | biostudies-arrayexpress