Uncovering novel ferroptosis regulators in pancreatic ductal adenocarcinoma (PDAC) using parallel Ribo-seq
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PROVIDER: PRJNA985711 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies and systematic chemotherapies are the most commonly-used standard treatment for PDAC patients diagonosed at advanced stages. However, drug resistance may arise as early as several weeks after chemotherapy initiation, thus limiting the therapeutic efficacy of chemotherapy reagents. Accumulating evidence has demonstrated that acquired tolerance to apoptotic cell death induced by cytotoxic drugs is one of the critical reasons for the failure of chemotherapy. Ferroptosis was originally identified as a unique form of programmed cell death, which is characterized by shrunk mitochondria accompanied with condensed membranes and decreased crista, in drug screens searching for small molecules that can selectively kill RAS-expressing cancer cells. Unlike apoptosis, ferroptosis is driven by iron-catalyzed excessive lipid peroxidation, ultimately leading to the rupture of plasma membrane and cell death. Recent studies indicated that ferroptosis induction can be a promising therapeutic strategy in cancer treatment since it not only can kill tumor cells directly but also can synergize with chemotherapy ,radiotherapy,targeted therapy and immunotherapy. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance.
2024-05-21 | GSE235336 | GEO
Project description:Uncovering novel ferroptosis regulators in pancreatic ductal adenocarcinoma (PDAC)
| PRJNA985702 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies and systematic chemotherapies are the most commonly-used standard treatment for PDAC patients diagonosed at advanced stages. However, drug resistance may arise as early as several weeks after chemotherapy initiation, thus limiting the therapeutic efficacy of chemotherapy reagents. Accumulating evidence has demonstrated that acquired tolerance to apoptotic cell death induced by cytotoxic drugs is one of the critical reasons for the failure of chemotherapy. Ferroptosis was originally identified as a unique form of programmed cell death, which is characterized by shrunk mitochondria accompanied with condensed membranes and decreased crista, in drug screens searching for small molecules that can selectively kill RAS-expressing cancer cells. Unlike apoptosis, ferroptosis is driven by iron-catalyzed excessive lipid peroxidation, ultimately leading to the rupture of plasma membrane and cell death. Recent studies indicated that ferroptosis induction can be a promising therapeutic strategy in cancer treatment since it not only can kill tumor cells directly but also can synergize with chemotherapy ,radiotherapy,targeted therapy and immunotherapy. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. Therefore, unravelling the underlying mechanisms responsible for reduced sensitivity to ferroptosis inducers, such as erastin or RSL3, may pave the way for designing effective therapeutic regimens for PDAC patients.
2024-05-21 | GSE235333 | GEO
Project description:Uncovering novel ferroptosis regulators in pancreatic ductal adenocarcinoma (PDAC) using parallel RNA-seq
| PRJNA985709 | ENA
Project description:Aberrant glycosylation involves multifaceted pathological and pathophysiological changes in pancreatic ductal adenocarcinoma (PDAC), including but not limited to conferring tumor cells the ability to resist cell death. Ferroptosis driven by lethal lipid peroxidation provides a targetable vulnerability to PDAC. However, the crosstalk between glycosylation and ferroptosis remains unclear. Here, we identified 4F2hc, a subunit of the glutamate-cystine antiporter system Xc–, its N-glycosylation is involved in PDAC ferroptosis by N- and O-linked glycoproteomics. Knockdown of SLC3A2 (gene name of 4F2hc) or blocking the N-glycosylation of 4F2hc potentiates ferroptosis sensitization of PDAC cells by impairing the activity of system Xc– manifested by a marked decrease in intracellular glutathione. To identify which glycosyltransferases are critical for glycosylation initiation during ferroptosis execution. We collected 207 glycosyltransferase genes (GTGs) and performed parallel RNA-seq to reveal that the glycosyltransferase B3GNT3 catalyzes the glycosylation of 4F2hc, which stabilizes the 4F2hc protein as well as its interaction with xCT. Additionally, upon the combination with a ferroptosis inducer, treatment with the classical N-glycosylation inhibitor tunicamycin (TM) markedly triggered the overactivation of lipid peroxidation and enhanced the sensitivity of PDAC cells to ferroptosis. Notably, we confirmed that genetic perturbation of SLC3A2 or combination treatment with TM markedly increased ferroptosis sensitivity in the orthotopic PDAC model. Clinically, high expression of 4F2hc and B3GNT3 contributes to the progression and poor survival of PDAC patients. Collectively, our findings reveal a previously unappreciated function of N-glycosylation of 4F2hc in ferroptosis and suggest that targeting glycosylated 4F2hc can induce susceptibility to ferroptosis in PDAC.
2023-07-12 | GSE207741 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-21 | GSE235337 | GEO
Project description:Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5, also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis.
2023-10-24 | PXD039998 | Pride
Project description:Determine methylation pattern in PDAC a genome-wide analysis was performed in a cohort of 167 PDAC and 29 adjacent pancreatic tissues samples using the Infinium 450k methylation arrays (Illumina). 167 pancreatic tumors (PDAC) x 29 adjacent -non tumor samples.
2014-07-08 | E-GEOD-49149 | biostudies-arrayexpress
Project description:The aim of the study was to characterize a common molecular mechanism for paclitaxel resistance in Patu-T and Suit-2.028 PDAC cell lines. Despite the ATP-binding cassette (ABC) trasnsporters were already shown to be involved in various chemo-resistant forms of cancers but not in PDAC, the most likely impact of ABCB1 overexpression in PDAC cell models was taken into account in this dataset.
2024-01-26 | PXD040930 | Pride
Project description:The presence of some malignancies, such as cancer, impacts on peripheral blood mononuclear cells (PBMCs) gene expression profiling, suggesting the potential suitability of these genes as diagnostic and prognostic markers. The objective of this study was to identify new markers in peripheral blood that differentiate between PDAC patients and healthy controls as a means of facilitating early detection of the disease. 18 patients with unresectable PDAC were recruited. The diagnosis of PDAC was based on a positive biopsy of the pancreatic mass during the surgery. 18 gender, age, and habits matched healthy controls were also included. Whole genome cDNA microarray hybridization of PBMC samples was performed to identify potential PDAC markers.
2013-08-12 | E-GEOD-49641 | biostudies-arrayexpress