Project description:Drug treatments often result in dramatic changes in gene expression. Thus, we used microarray to uncover gene expression effects of fluvastatin treatment on ASPC1-GFP PDAC cells.
Project description:Fluvastatin has been identified as novel inhibitors of metastasis in pancreatic cancer. In multiple in vivo and in vitro experiments the compounds phenotypic effects was validated. Since under drug treatment the transcriptomic changes in examined cell lines were rather small, we expected the underlying mechanistic effect to be on the level of the proteome and more importantly the phospho-proteome. To evaluate this assumption we performed label-free full proteome and phosphoproteomics experiments on Fluvastatin treated ASPC1 cells.
Project description:Cisplatin is a broad-spectrum anticancer drug, which is estimated to be administered to 40-80% of patients undergoing chemotherapy. However, its clinical utility is often limited due to factors that include acquired resistance of cancer cells to cisplatin. Because cisplatin is currently evaluated as a prospective agent for combined chemotherapy of pancreatic ductal adenocarcinoma (PDAC), we have investigated mechanisms involved in the acquired resistance of PDAC cells to cisplatin using gene expression study of two different parental-resistant pairs of PDAC cell lines. We have developed cisplatin-resistant cell lines AsPC1-R and BxPC3-R from their parental PDAC cell lines AsPC1 and BxPC3, respectively, by culturing them in medium with step-wise increasing concentration of cisplatin. Parental and resistant pairs of PDAC cells were analyzed by whole-transcript gene expression analysis.
Project description:Clinical data of patients suffering from COVID-19 have indicated that statin therapy, used to treat hypercholesterolemia, is associated with a better clinical outcome. We therefore investigated the effect of statins on SARS-CoV-2 infection in human lung cells and found that fluvastatin inhibited coronavirus infection, while other tested statins did not. Fluvastatin inhibited high and low pathogenic coronaviruses in vitro and ex vivo in a dose-dependent manner. Proteomic analyses of infected versus uninfected lung epithelial cells treated with fluvastatin, simvastatin, or rosuvastatin revealed that all tested statins modulated the cholesterol synthesis pathways without compromising the innate antiviral immune response. Strikingly, fluvastatin treatment uniquely affected the proteome of SARS CoV 2 infected cells, specifically downregulating proteins that modulate protein translation and viral replication. These results suggest that statin therapy poses no additional risk to individuals exposed to SARS-CoV-2 and that fluvastatin may have a moderate beneficial effect on SARS CoV-2 infection by modulating protein translation.
Project description:The goal of this study was to determine the gene expression changes following fluvastatin treatment in t(4;14)-positive multiple myeloma (MM) cell lines. To this end, two cell lines (KMS11 and NCI-H929) were treated with fluvastatin (2 micromolar) or ethanol as a solvent control for 24 hours. RNA was extracted and prepared for high-throughput sequencing in duplicate.
Project description:Background: Cholesterol pathway inhibition by statins prevents breast cancer development in mouse models of breast cancer but their efficacy is not very high (about 50%) . Therefore, the goal of this study is to investigate if the fluvastatin mediated upregulation in the steroid biosynthesis pathway genes limit the efficacy of statin chemoprevention. Methods: A published gene signature of statin resistance was validated in cell line-based models of inherent and acquired resistance during breast cancer. These signatures were next validated in a mouse model of hormone receptor negative breast cancer. Results: We found more than 70% of a published multi-gene fluvastatin resistance signature to be significantly upregulated in an inherently resistant cell line relative to fluvastatin sensitive cell line. We found this inherent statin resistance gene signature to be also shared with the signature of acquired resistance to fluvastatin (13 / 23 total genes). These 13 inherent resistance genes and 10 additional genes mapped to 2 of the top 3 deregulated pathways that are steroid-, and terpenoid backbone- biosynthesis pathway. Next, we tested if one or multiple genes of statin resistance signature, could predict efficacy of statin chemoprevention in the SV40 C3TAg transgenic mouse model. We found upregulation of a large number (19/24) of genes in the tumor bearing mammary glands, suggesting that upregulation of these pathways drives resistance to statin chemoprevention. A subset of 13-genes from this panel was significantly associated with response to statin treatment, as was the expression level of HMGCR alone in a mouse model of breast cancer. Lastly, we studied if a 10-day period of fluvastatin treatment to SV40C3 TAg mice, can also trigger the upregulation of these genes and provide an early signal of statin resistance. These experiments showed that a 10-day period is insufficient to cause a feedback upregulation in steroid biosynthesis pathway genes and thus cannot be used as an early biomarker to detect resistance to fluvastatin. Conclusions: High basal or restorative upregulation in the steroid biosynthesis pathway gene expression after fluvastatin treatment appears to be strongly associated with resistance to statin chemoprevention for breast cancer and may serve as a biomarker to identify patients that are most likely to respond to statins or develop resistance.
Project description:Human pancreatic ductal adenocarcinoma (PDAC) derived cancer-associated fibroblast (CAF) treated or not with isorhamnetin We used microarrays to detail the global hallmarks, gene ontology, and KEGG pathway terms affected by isorhamnetin treatment of CAF derived from human PDAC
Project description:USP21 promotes PDAC tumor cells to bypass KRAS* dependency. To dissect the molecular mechanism, we conducted RNA-seq analysis comparing iKPC cancer cells overexpressing GFP, wildtype USP21 and enzyme-dead USP21 at day 3 after KRAS* extinction. KRAS*-expressing iKPC cells with GFP overexpression are positive control.
Project description:The present gene expression array study of fluvastatin effects on monocytes from SLE patients show that fluvastatin has a global anti-inflammatory effect on monocytes, which includes attenuated expression of several proinflammatory cytokines, and regulated expression of molecules mediating lipoprotein signaling and cholesterol metabolism, as well as atherosclerosis and inflammatory signaling.
Project description:The current study analyzed the altered expression profiles of genes that are responsible for fluvastatin-induced breast cancer cell death in MCF-7 cells (ER+ve luminal breast cancer cells). Some of these altered gene expressions were further inter connceted to various pathways which may eventually be recognised as drug targets/ biomarkers in statin-sensitve breast cancer patients. To understand the differential gene expression profile in fluvastatin treated (24 h) malignant breast cancer cells with untreated malignant breast cancer cells.