NOXA dependent induction of apoptosis in pancreatic cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA623399 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11492000.fastq.gz | Fastqsanger.gz | |||
| SRR11492001.fastq.gz | Fastqsanger.gz | |||
| SRR11492002.fastq.gz | Fastqsanger.gz | |||
| SRR11492003.fastq.gz | Fastqsanger.gz | |||
| SRR11492004.fastq.gz | Fastqsanger.gz |
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Project description:The dolichyl-diphosphooligosaccharide-protein glycosyltransferase non-catalytic subunit (DDOST) is a key component of the oligosaccharyltransferase complex catalyzing N-linked glycosylation in the endoplasmic reticulum lumen. DDOST is associated with several cancers and congenital disorders of glycosylation. However, its role in pancreatic cancer remains elusive, despite its enriched pancreatic expression. Using quantitative mass spectrometry, we identify 30 differentially expressed proteins and phosphopeptides (DEPs) after DDOST knockdown in the pancreatic ductal adenocarcinoma (PDAC) cell line PA-TU-8988T. We evaluated DDOST / DEP protein-protein interaction networks using STRING database, correlation of mRNA levels in pancreatic cancer TCGA data, and biological processes annotated to DEPs in Gene Ontology database. The inferred DDOST regulated phenotypes were experimentally verified in two PDAC cell lines, PA-TU-8988T and BXPC-3. We found decreased proliferation and cell viability after DDOST knockdown, whereas ER-stress, ROS-formation and apoptosis were increased. In conclusion, our results support an oncogenic role of DDOST in PDAC by intercepting cell stress events and thereby reducing apoptosis. As such, DDOST might be a potential biomarker and therapeutic target for PDAC.
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Project description:Non-small cell lung cancer (NSCLC) is highly malignant with limited treatment options due to the inherent tumoral heterogeneity and acquired resistance towards chemotherapy and immunotherapy. RG7388 was previously reported to have anticancer activity against TP53WT NSCLC which was designed as MDM2 inhibitor triggering p53/PUMA axis-dependent apoptosis. However, RG7388 exhibited p53-independent anticancer effect against TP53mutant NSCLC in our current research, the underlying mechanisms of which were still uncertain. Here, we reported that RG7388 specifically induced NOXA/Caspase-3 axis dependent apoptosis and gasdermin E (GSDME)-mediated secondary pyroptosis in TP53mutant NSCLC using in silico and multiple biological methods. Mechanically, we identified accumulated reactive oxygen species (ROS) served as the pivotal factor in NOXA upregulation and p38 MAPK pathway activation in RG7388 treated TP53mutant NSCLC by using two ROS scavengers N-acetylcysteine (NAC) and Ferrostatin-1 (Fer-1) respectively. Furthermore, pharmacologic inhibition of p38 MAPK signaling by SB203580 rescued RG7388 induced ROS-dependent NOXA accumulation and subsequent apoptosis and pyroptosis, thus suggesting a leading role of ROS/phosphorylated p38 MAPK (p-p38)/NOXA/Caspase-3 axis in RG7388 induced TP53mutant NSCLC cell death. Taken together, our work unraveled a novel mechanism of selective targeting of mutant p53 derived cancers via ROS/p-p38-mediated NOXA accumulation that could have potential therapeutic implications given the relative lack of direct mutant p53 targeting strategies in cancer. Moreover, A strong positive correlation between p-p38 and NOXA expression was confirmed by using an NSCLC tissue microarray and immunohistochemical (IHC) staining. Clinical data analysis suggested that the p-p38/NOXA axis could serve as a potential indicator for predicting overall survival (OS) in NSCLC patients.
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Project description:The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.
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Project description:The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.
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Project description:Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine (Gem) is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G2/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to Gem induced apoptosis, a mechanism mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and Gem resulted in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase 3 and increased Bax/Bcl2 ratio. Gene profiling studies demonstrated that this combination down regulated Akt-mTOR signaling pathway, which was confirmed by western blot analyses. There was also a down regulation of vascular endothelial growth factor (VEGF) and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31 positive blood vessels, and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis. Case control dual channel design
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