Effects of a novel HBP inhibitor, FR054, and Gemcitabine in pancreatic cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223303 | GEO | 2023/05/08
REPOSITORIES: GEO
Similar Datasets
Project description:We generated gemcitabine resistant subclones from the human pancreatic cancer cell line BxPC3 using chronic low dose exposure to gemcitabine. Three gemcitabine resistant subclones (BxGR-80C, BxGR-120C and BxGR-360C) were sequenced in addition to BxPC3 cells.
2021-12-21 | E-MTAB-11186 | biostudies-arrayexpress
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: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. 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.
2023-05-20 | GSE232549 | GEO
Project description:We reported the transcriptional effects of gemcitabine, genistein and the combined gemcitaibe/gensitein treatments on two pancreatic cancer cell lines MiaPaCa2 and PANC1. The overall purpose of the study to understand the underlying mechanism of genistein chemoenhancing function.
2019-12-31 | GSE97766 | GEO
Project description:Effects of a novel HBP inhibitor, FR054, and Gemcitabine in pancreatic cancer cells
| PRJNA925548 | ENA
Project description:To better understand the biochemical changes associated with castrate resistant prostate cancer (CRPC), we developed a pathway-based integrated analytical method to examine prostate cancer (PCa) gene expression and metabolomic datasets and found distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) between androgen dependent (AD) PCa and CRPC, with elevated expression of HBP genes in primary PCa associated with poor clinical outcome. Expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in AD PCa while relatively diminished in CRPC.Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased aggressiveness, while GNPNAT1 knockdown decreased proliferation in AD PCa cells. Each scenario was accompanied by specific bio-energetic and molecular alterations. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine significantly enhanced efficacy of the anti-androgen enzalutamide in CRPC cells by repressing NF-Y driven cell cycle regulators. Our study demonstrates the therapeutic value of targeting altered metabolic pathways in lethal PCa.
2016-09-20 | GSE50661 | GEO
Project description:mRNA-seq of gemcitabine resistant pancreatic cancer cell line subclones derived from BxPC3
| PRJEB48965 | ENA
Project description:Tumorigenesis is characterised by changes in transcriptional regulation and the androgen receptor (AR) has been identified as a key driver in prostate cancer. In this study, we show that the hexosamine biosynthetic pathway (HBP) genes are overexpressed in clinical prostate cancer and androgen-regulated in cell-lines. HBP senses metabolic status of the cell and produces an essential substrate for O-GlcNAc transferase (OGT), which regulates target proteins via glycosylation. Using immunohistochemistry, we found that OGT is up-regulated in the protein level in prostate cancer (n=1987) and its expression correlates with high Gleason Score, pT and pN stages and biochemical recurrence (for all, p<0.0001). Both a small molecule inhibitor and siRNAs targeting OGT decreased prostate cancer cell growth. Microarray profiling revealed that the principal effects of the OGT inhibitor in prostate cancer cells are on cell cycle progression and DNA replication. We identified MYC as a candidate upstream regulator of these genes and found that OGT inhibitor caused a dose-dependent loss of c-MYC protein but not mRNA in cell lines. Finally, we observed a statistically significant co-expression between c-MYC and OGT in human prostate cancer samples (n=1306, p=0.0012). Total RNA was extracted and experiment has three biological replicates for each condition, conditions are: 12 hours ST045849, 24 hours ST045849, 12 hours vehicle, 24 hours vehicle, 12 hours siOGT, 24 hours siOGT, 12 hours scrambled, 24 hours scrambled
2013-05-30 | E-GEOD-44624 | biostudies-arrayexpress
Project description:We use RNA Sequencing to analyze the potential molecular mechanisms in human pancreatic cancer cell line BxPC3 cells after erastin and vitamin C treatment for 48h.
2021-12-24 | GSE192362 | GEO
Project description:The hexosamine biosynthetic pathway (HBP) is a pathway that requires glucose using approximately 3% ~ 5% of total glucose coming into cells. HBP synthesizes UDP-GlcNAc using not only glucose but also various metabolic products such as those amino acid, fatty acid and nucleotide. O-GlcNAcylation by Ogt is considered the act as a nutrient sensor because the amount of UDP-GlcNAc is influenced by various metabolites. Therefore, when the balance of O-glcnacylation is broken, it induces diseases such as cancer or neurological diseases or affects the differentiation of cells. Bone homeostasis is regulated by osteoblasts that produce bone and osteoclasts that resorb bone. Disruption of this balance leads to diseases such as osteoporosis. Previous studies reported that osteoblast differentiation was inhibited by excessive O-GlcNAcylation. Increased o-glcnacylation of runx2 induced bone homeostasis imbalance by reducing the transcriptional activity of runx2 and mRNA expression of the target gene of runx2 involved in osteoblast differentiation. However, how O-GlcNAcylation regulates differentiation of osteoclast remains unclear. So, the goals of our study are to describe expression changes in genes expression associated with O-GlcNAcylation during RNAKL-mediated osteoclast differentiation.
2021-06-08 | GSE176265 | GEO