Sirt6 Oncogene Mediates PI3K/Akt Signaling Activation in Diffuse Large B-Cell Lymphoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA560560 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9989150_1.fastq.gz | Fastqsanger.gz | |||
| SRR9989150_2.fastq.gz | Fastqsanger.gz | |||
| SRR9989145_1.fastq.gz | Fastqsanger.gz | |||
| SRR9989145_2.fastq.gz | Fastqsanger.gz | |||
| SRR9989146_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose:Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppress and augment tumor growth. This experiment aimed to document the Sirt6 expression and functions in diffuse large B-cell lymphoma (DLBCL). Methods:Immunohistochemistry was conducted to assess the expression of Sirt6 on paraffin-embedded tissues from 70 DLBCL patients and 35 reactive hyperplasia patients with informed contents. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. shSirt6 transfected or shControl transfected LY1 cell samples were performed RNA sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID-Beige mice to establish xenograft models. Results:Sirt6 is found to be highly expressed and predictive of negative prognoses in DLBCL. Sirt6-deprived DLBCL cells demonstrated augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation and were noted to have arrested cell cycle progression between the G2 and M phases. In accordance with the gene set enrichment analysis (GSEA) according to RNA-sequencing, PI3K signaling along with phosphorylation of its downstream targets (including mTOR and AKT) was reduced upon Sirt6 downregulation. Xenograft models that were infected with Sirt6-knockdown vectors demonstrated suppressed tumor growth and lower rates of c-Myc/Ki-67 staining. Conclusion: These findings provide mechanistic insights into the oncogenic activity of Sirt6 for the first time.
2019-08-17 | GSE135914 | GEO
Project description:Diffuse midline glioma (DMG) is a uniformly fatal pediatric, adolescent, and young adult cancer diagnosed in the midline structures of the brain. PI3K/Akt signaling is an overarching contributor to the poor outcomes of DMG patients due to their dependance on insulin and recurring mutations and amplifications in PI3K/Akt genes. Paxalisib (GDC-0084) is a potent PI3K/Akt inhibitor developed to penetrate the brain’s protective blood-brain barrier (BBB). We performed paxalisib regimen optimization by assessment of blood glucose levels, analysis in vivo pharmacokinetics/pharmacodynamics properties, and employed DMG patient derived xenograft (PDX) mouse models to determine preclinical efficacy. To identify novel combination strategies, we conducted high-resolution quantitative phosphoproteomics of DMG cells treated with paxalisib. Elevated blood glucose levels promoting hyperglycemia was seen in mice using paxalisib 10 mg/kg/day (~mouse equivalent human maximum tolerated dose- NCT03696355). Whereas 5 mg/kg/day, or 5mg/kg/b.i.d. (twice daily) non-significantly increased blood glucose levels compared to controls. Pharmacokinetic analysis of mouse tissues showed 5 mg/kg/b.i.d. increased paxalisib acumination in the brainstem, suppressing PI3K/Akt signaling to significantly extend the survival of DMG PDX models compared to all other regimens; a survival benefit amplified when combined with the anti-glycemic therapy metformin. Phosphoproteomic profiling identified increased Protein kinase C (PKC) signaling following paxalisib treatment. The combination of paxalisib and enzastaurin (PKC inhibitor) synergistically extended the survival of PDX models. Our optimized dosing regimen increased the preclinical benefits of paxalisib, with the combination of paxalisib with metformin, or paxalisib with enzastaurin, heralding rationally designed combination strategies for the treatment of DMG
2024-02-20 | PXD036114 | Pride
Project description:Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be deM-oM-,M-^Aned by gene expression proM-oM-,M-^Aling. However, even within these deM-oM-,M-^Aned subtypes, heterogeneity prevails. To further elucidate the pathogenesis of these entities, we determined the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) in 248 primary DLBCL patient samples. These analyses revealed that loss of PTEN was detectable in 55% of germinal center B-cell-like (GCB) DLBCLs, whereas this abnormality was found in only 14% of non-GCB DLBCL patient samples. In GCB DLBCL, the PTEN status was inversely correlated with activation of the oncogenic PI3K/ protein kinase B (AKT) pathway in both DLBCL cell lines and primary patient samples. Reexpression of PTEN induced cytotox- icity in PTEN-deM-oM-,M-^Acient GCB DLBCL cell line models by inhibiting PI3K/AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs. PI3K/AKT inhibition induced down-regulation of the transcription factor MYC. Reexpression of MYC rescued GCB DLBCL cells from PTEN-induced toxicity, identifying a regulatory mechanism of MYC expression in DLBCL. Finally, pharmacologic PI3K inhibition resulted in toxicity selectively in PTEN-deM-oM-,M-^Acient GCB DLBCL lines. Collectively, our results indicate that PTEN loss deM-oM-,M-^Anes a PI3K/ AKT-dependent GCB DLBCL subtype that is addicted to PI3K and MYC signaling and suggest that pharmacologic inhibition of PI3K might represent a promising therapeutic approach in these lymphomas. This GEO dataset is comprised of a) GEP measurements for 34 primary DLBCL patient samples plus two reference samples, b) 8 paired GEP measurements of the HT DLBCL cell line and c) aCGH measurements for two DLBCL cell lines in addition to previously published cell lines in GSE43272 (i.e., Sample GSM1059798). All of these data were used in the paper cited below.
2013-07-09 | E-GEOD-45495 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous diagnostic category with distinct molecular subtypes that can be defined by gene expression profiling. However, even within these defined subtypes, heterogeneity prevails. To further elucidate the pathogenesis of these entities, we determined the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) in 248 primary DLBCL patient samples. These analyses revealed that loss of PTEN was detectable in 55% of germinal center B-cell-like (GCB) DLBCLs, whereas this abnormality was found in only 14% of non-GCB DLBCL patient samples. In GCB DLBCL, the PTEN status was inversely correlated with activation of the oncogenic PI3K/ protein kinase B (AKT) pathway in both DLBCL cell lines and primary patient samples. Re-expression of PTEN induced cytotoxicity in PTEN-deficient GCB DLBCL cell line models by inhibiting PI3K/AKT signaling, indicating an addiction to this pathway in this subset of GCB DLBCLs. PI3K/AKT inhibition induced down-regulation of the transcription factor MYC. Re-expression of MYC rescued GCB DLBCL cells from PTEN-induced toxicity, identifying a regulatory mechanism of MYC expression in DLBCL. Finally, pharmacologic PI3K inhibition resulted in toxicity selectively in PTEN-deficient GCB DLBCL lines. Collectively, our results indicate that PTEN loss defines a PI3K/ AKT-dependent GCB DLBCL subtype that is addicted to PI3K and MYC signaling and suggest that pharmacologic inhibition of PI3K might represent a promising therapeutic approach in these lymphomas.
2013-07-09 | GSE45495 | GEO
Project description:Diffuse midline glioma (DMG) is a uniformly fatal pediatric, adolescent, and young adult cancer diagnosed in the midline structures of the brain. PI3K/Akt signaling is an overarching contributor to the poor outcomes of DMG patients due to their dependance on insulin and recurring mutations and amplifications in PI3K/Akt genes. Paxalisib (GDC-0084) is a potent PI3K/Akt inhibitor developed to penetrate the brain’s protective blood-brain barrier (BBB). We performed paxalisib regimen optimization by assessment of blood glucose levels, analysis in vivo pharmacokinetics/pharmacodynamics properties, and employed DMG patient derived xenograft (PDX) mouse models to determine preclinical efficacy. To identify novel combination strategies, we conducted high-resolution quantitative phosphoproteomics of DMG cells treated with paxalisib. Elevated blood glucose levels promoting hyperglycemia was seen in mice using paxalisib 10 mg/kg/day (~mouse equivalent human maximum tolerated dose- NCT03696355). Whereas 5 mg/kg/day, or 5mg/kg/b.i.d. (twice daily) non-significantly increased blood glucose levels compared to controls. Pharmacokinetic analysis of mouse tissues showed 5 mg/kg/b.i.d. increased paxalisib acumination in the brainstem, suppressing PI3K/Akt signaling to significantly extend the survival of DMG PDX models compared to all other regimens; a survival benefit amplified when combined with the anti-glycemic therapy metformin. Phosphoproteomic profiling identified increased Protein kinase C (PKC) signaling following paxalisib treatment. The combination of paxalisib and enzastaurin (PKC inhibitor) synergistically extended the survival of PDX models. Our optimized dosing regimen increased the preclinical benefits of paxalisib, with the combination of paxalisib with metformin, or paxalisib with enzastaurin, heralding rationally designed combination strategies for the treatment of DMG.
2024-02-20 | GSE211565 | GEO
Project description:The Ras/ERK and PI3K/AKT pathways differentially regulate the oncogene ERG in prostate cancer resulting in differential transcriptional profile
2021-05-27 | GSE164859 | GEO
Project description:Diffuse midline glioma (DMG) is a uniformly fatal pediatric, adolescent, and young adult cancer diagnosed in the midline structures of the brain. PI3K/Akt signaling is an overarching contributor to the poor outcomes of DMG patients due to their dependance on insulin and recurring mutations and amplifications in PI3K/Akt genes. Paxalisib (GDC-0084) is a potent PI3K/Akt inhibitor developed to penetrate the brain’s protective blood-brain barrier (BBB). We performed paxalisib regimen optimization by assessment of blood glucose levels, analysis in vivo pharmacokinetics/pharmacodynamics properties, and employed DMG patient derived xenograft (PDX) mouse models to determine preclinical efficacy. To identify novel combination strategies, we conducted high-resolution quantitative phosphoproteomics of DMG cells treated with paxalisib. Elevated blood glucose levels promoting hyperglycemia was seen in mice using paxalisib 10 mg/kg/day (~mouse equivalent human maximum tolerated dose- NCT03696355). Whereas 5 mg/kg/day, or 5mg/kg/b.i.d. (twice daily) non-significantly increased blood glucose levels compared to controls. Pharmacokinetic analysis of mouse tissues showed 5 mg/kg/b.i.d. increased paxalisib acumination in the brainstem, suppressing PI3K/Akt signaling to significantly extend the survival of DMG PDX models compared to all other regimens; a survival benefit amplified when combined with the anti-glycemic therapy metformin. Phosphoproteomic profiling identified increased Protein kinase C (PKC) signaling following paxalisib treatment. The combination of paxalisib and enzastaurin (PKC inhibitor) synergistically extended the survival of PDX models. Our optimized dosing regimen increased the preclinical benefits of paxalisib, with the combination of paxalisib with metformin, or paxalisib with enzastaurin, heralding rationally designed combination strategies for the treatment of DMG.
2024-02-20 | GSE246057 | GEO
Project description:Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Ka/d) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor kappa-B (NF-kB) signaling, prompting us to combine AZD8835 with the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib. This combination was highly synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors.
2017-07-01 | GSE92619 | GEO
Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress
Project description:Preclinical Optimization of the PI3K/Akt inhibitor Paxalisib for the Treatment of Diffuse Midline Glioma
| PRJNA870917 | ENA