Gene Expression Profiling of OPM2 treatment with VS-5584 (SB2343).
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84862 | GEO | 2016/07/27
SECONDARY ACCESSION(S): PRJNA335389
REPOSITORIES: GEO
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Project description:The PI3K/mTOR pathway is a constitutively active in multiple myeloma. Single inhibition of mTOR usually confers reactivation of the pathway. VS-5584 (SB2343) is a bispecific PI3K/mTOR inhibitor which effectively and specifically inhibits the target pathways and shows potent anti-myeloma activity. We utilised a gene microarray analysis to analyse and identify the genes that were sensitively regulated by VS-5584 treatment in OPM2. OPM2 cells were either treated with DMSO(drug solvent) or with 125nM of VS-5584(SB2343) which is half the IC50 concentration of the drug at 48h in OPM2 cells. The cells were harvested at 24h in order to detect the regulation of relatively early response genes.
2016-07-27 | E-GEOD-84862 | biostudies-arrayexpress
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Project description:Forkhead Box M1 (FOXM1) is a promising molecular target for high-risk multiple myeloma and relapse and refractory myeloma, but whether FOXM1 is essential in myeloma has not yet been established. To address this knowledge gap, we used Western blotting to measure FOXM1 protein levels in 11 human myeloma cell lines (HMCLs) and then chose the two lines expressing the largest amount of the transcription factor, OPM2 and Delta47, for gene editing using CRISPR-Cas9. In both cases, two independent FOXM1-deficient daughter lines, designated KO-1 and KO-2, were generated. They contained 2 different 10-bp deletions at the target site of their respective guide RNA in case of OPM2 and a 10-bp deletion and 1-bp insertion in case of Delta47. Western analysis confirmed the lack of FOXM1 in all knockout clones. FOXM1-deficient myeloma cells proliferated more slowly than their parental counterparts containing normal levels of FOXM1. Moreover, we added back FOXM1 to FOXM1-KO cells by transfection of a constitutively expressed FOXM1c cDNA gene. The reconstituted OPM2 and Delta47 cells, designated FOXM1 KO-R contained high amounts of FOXM1 protein. Here, we used these cell lines to investigate the role of FOXM1 in regulating the gene expression in multiple myeloma.
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Project description:Analysis of the effects of a dual specificity PI3K/mTOR inhibitor on two human ovarian cell lines, OV2008 and MCAS. Results provide insight into the adaptive response to PI3K/mTOR inhibition in matrix attached ovarian cancer cells. The PI3K/mTOR-pathway is the most commonly deregulated pathway in epithelial cancers and thus represents an important target for cancer therapeutics. Here we show that dual inhibition of PI3K/mTOR in ovarian cancer 3D-spheroids leads to death of the inner matrix-deprived cells, whereas matrix-attached cells are resistant. Resistance is associated with up-regulation of a cellular survival program that involves both FOXO-regulated transcription and a novel translational resistance mechanism resulting in specific up-regulation of IRES-mediated, cap-independent translation. Inhibition of any of several up-regulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to dual PI3K/mTOR inhibition. These results demonstrate that acute adaptive response to PI3K/mTOR inhibition resembles well-conserved adaptive response to nutrient and growth factor deprivation and how development of rational drug combinations can bypass resistance mechanisms. Total RNA was isolated 6h and 24h after treatment with 1 M-NM-<M NVP-BEZ235 or DMSO vehicle control from 3D grown structures
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Project description:Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. However, the use of mTOR inhibitors as single agents have shown limited clinical efficacy in relation with drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we evaluated the antitumor activity of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in primary MCL cells. We found that dual PI3K/mTOR inhibitor modulated angiogenesis, tumor invasiveness and cytokine signaling compared to a mTOR inhibitor and a pan-PI3K inhibitor in MCL. We used microarrays to compare the effect of these three compounds in MCL and identified distinct classes of down-regulated genes modulated by each compound.
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Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT
The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H).
This model is described in the article:
Computational Modelling of the Metabolic States Regulated by the Kinase Akt.
Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L.
Frontiers in Systems Biology. 2012 Oct 13
Abstract:
Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.
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