Ikarugamycin blocks the glycolysis in pancreatic cancer
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ABSTRACT:
PROVIDER: PRJNA494233 | ENA |
REPOSITORIES: ENA
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Project description:Analysis of gene alterations in PANC-1 cells treated with different concentration of Ikarugamycin (Ika). A broad variety of biological activities of IKA has been reported, such as immune regulation, cytotoxic properties, anti-tumor effects and other pharmacological effects. This study provides insight into molecular basis of Ika in pancreatic cancer.
2018-10-02 | GSE120713 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. It thrives in a nutrient-poor environment; however, the mechanisms by which PDAC cells undergo metabolic reprogramming to adapt and survive in metabolic stress are still poorly understood. Here, we show that microRNA-135 is significantly increased in PDAC patient samples compared to adjacent normal tissue and represses aerobic glycolysis. Mechanistically, we found that miR-135 accumulates specifically in response to glutamine deprivation and requires ROS-dependent activation of mutant p53, which directly promotes miR-135 expression. Functionally, we found miR-135 targets phosphofructokinase-1 (PFK1) and inhibits aerobic glycolysis, thereby promoting the utilization of glucose to support the tricarboxylic acid (TCA) cycle. Consistently, miR-135 deficient PDAC cells preferentially use glutamine carbon to replenish the TCA cycle, and miR-135 silencing sensitizes PDAC cells to glutamine deprivation and represses tumour growth in vivo. Consistent with these findings, patient pancreatic cancer tissue displays decreased PFK1 level compared to adjacent normal tissue. Together, these results identify a mechanism used by PDAC cells to survive the nutrient-poor tumour microenvironment, and also provide insight regarding the role of mutant p53 and miRNA in pancreatic cancer cell adaptation to metabolic stresses.
2019-02-27 | GSE125538 | GEO
Project description:CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing
| PRJNA1061762 | ENA
Project description:Metabolomics analysis of serum exosomes isolated from pancreatic cancer patients and healthy controls.
2019-04-06 | MSV000083669 | GNPS
Project description:Pancreatic cancer is one of the deadliest human malignancies, with a survival rate less than 10%. Traditional modes of therapy have proven ineffective in the treatment of pancreatic cancer, highlighting the need to further understand the basic biology of the disease in order to identify new treatment modalities. Previously, our group showed that the epigenetic regulator Bmi1 is required for the initiation of pancreatic cancer in mice. In murine models of PDAC, mice lacking pancreatic Bmi1 expression do not develop precancerous lesions, despite oncogene expression. In this work, we sought to determine the role of Bmi1 in later stages of pancreatic tumor development. Using a CRISPR/Cas9 strategy, we deleted Bmi1 in primary human pancreatic caner cells and created clonal lines. When used in a subcutaenous tumor growth assay, those cells lacking BMI1 expression formed tumors that grew significantly smaller than controls. To query the mechanism of BMI1 action in pancreatic cancer growth, we used RNA sequencing to compare those pancreatic cancer cells with and without BMI1 expressed. This revealed that Bmi1 controls the gene expression of glycolysis and cell proliferation pathways, likely the reason for its requirement in pancreatic tumor growth. Overall, we found that Bmi1 is required in pancreatic tumor progression, and that it controls gene expression in both glycolysis and cell proliferation.
2023-06-30 | GSE149981 | GEO
Project description:Mitogen activated protein kinase kinase kinase 1 (MAP3K1), is involved in various cancer signaling networks including the NF-B, JNK, ERK, and p38 pathways. Functioning as a signaling kinase in these oncogenic pathways, MAP3K1 contributes to tumor growth and metastasis. Additionally, higher transcript levels of MAP3K1 in pancreatic patient tumors is associated with poorer 5-year survival, suggesting MAP3K1 is an attractive therapeutic target. Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKK), an important phosphorylation target of MAP3K1, was shown to be important in pancreatic cancer (PC) disease onset and progression. We previously reported a quinoxaline analog, Analog 84, which inhibits IKK phosphorylation and downstream NF-B pathway activation. To improve the metabolic stability and bioavailability of Analog 84, we developed 51-106, which moved -F atom to block a site of potential metabolism. Using a chemoproteomics approach for kinome profiling, KiNativTM, we show 51-106 selectively binds to MAP3K1 in an ATP-competitive manner. Follow up studies show 51-106 inhibits downstream phosphorylation of IKK and blocks TNF-induced MAP3K1-IKK-mediated NF-B activity. Treatment of PC cell lines MiaPaCa2 and PANC-1 with 51-106 inhibits cell growth and migration with low micromolar potency. Utilizing 51-106 as a tool to study MAP3K1 signaling, we use phosphoproteomics analysis to show MAP3K1 inhibition leads to a dose dependent decrease in NPM1 T199 phosphorylation, suggesting NPM1 may play a role in MAP3K1 signaling. We observe a dose-dependent S-phase arrest in cells treated with 51-106, potentially linking MAP3K1 inhibition to a dysfunctional DNA damage response. Consistent with this observation, in combination studies, 51-106 synergistically inhibited growth with gemcitabine in LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC) cell lines in vitro and in KPC syngeneic orthotopic implantation mouse model of pancreatic cancer in vivo. Our data indicated that MAP3K1 inhibition may represent a promising therapeutic in PC. These findings underscore the need for further investigation into the molecular interactions and downstream effects of the MAP3K1-NPM1 signaling axis.
2025-05-26 | PXD055363 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of, and potential as a therapeutic target for, PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that the PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.
2024-03-09 | GSE223146 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of, and potential as a therapeutic target for, PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that the PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.
2024-03-09 | GSE223133 | GEO