Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Aurora kinase inhibition triggers senescence in human melanoma cells

ABSTRACT: Phenotypically, there is a heterogeneous response of cancer cells to chemotherapy or targeted therapy. While therapeutically much attention is focused on cell death, there is growing evidence suggesting that a subpopulation of cancer cells undergo therapy-induced senescence. Depending on the therapy, dose and timing, senescence may be a dominant phenotype over cell death. An integrated FACS approach identified two types of therapy-induced senescence in human melanoma cells, irreversible senescence induced by Aurora kinase inhibition vs. transient senescence induced by B-RAF kinase inhibition. Autophagy and ER stress response precede and are required for therapy-induced senescence in cancer cells, mirroring their functions in normal cells undergoing oncogene-induced senescence. Importantly, autophagy serves a survival pathway for senescent cancer cells. Antagonizing autophagy converts therapy-induced senescence into cell death but paradoxically promotes cell proliferation or quiescence. Our work calls for a rationale-based design of combination therapy for cancer treatment that should lead to a greater synergy. There are three or four replicates per treatment per time point.

ORGANISM(S): Homo sapiens

SUBMITTER: Gao Zhang

PROVIDER: E-GEOD-38466 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

Aurora kinase inhibition triggers senescence in human melanoma cells

Project description:Phenotypically, there is a heterogeneous response of cancer cells to chemotherapy or targeted therapy. While therapeutically much attention is focused on cell death, there is growing evidence suggesting that a subpopulation of cancer cells undergo therapy-induced senescence. Depending on the therapy, dose and timing, senescence may be a dominant phenotype over cell death. An integrated FACS approach identified two types of therapy-induced senescence in human melanoma cells, irreversible senescence induced by Aurora kinase inhibition vs. transient senescence induced by B-RAF kinase inhibition. Autophagy and ER stress response precede and are required for therapy-induced senescence in cancer cells, mirroring their functions in normal cells undergoing oncogene-induced senescence. Importantly, autophagy serves a survival pathway for senescent cancer cells. Antagonizing autophagy converts therapy-induced senescence into cell death but paradoxically promotes cell proliferation or quiescence. Our work calls for a rationale-based design of combination therapy for cancer treatment that should lead to a greater synergy. There are three or four replicates per treatment per time point.

2016-09-01 | E-GEOD-50474 | biostudies-arrayexpress

Aurora kinase inhibition triggers senescence in human melanoma cells

2016-09-01 | GSE50474 | GEO

Aurora kinase inhibition triggers senescence in human melanoma cells

2015-06-05 | GSE38466 | GEO

Modulation of the ATM/autophagy pathway tips the balance between senescence and apoptosis in response to 20A ligand

Project description:G-quadruplex ligands (G4L) exert their anti-proliferative effect through telomere-dependent and -independent mechanisms, but the inter-relationship between autophagy, cell growth arrest and cell death induced by these ligands remains largely unexplored. 20A is a 2,4,6-triarylpyridine derivative that binds to G4-DNA with fair to excellent selectivity. Here, we demonstrate that this compound impairs cancer cell viability through induction of senescence and apoptotic cell death in a p53-independent manner. In vivo results corroborate those obtained in in vitro, showing that 20A elicits an important tumor growth inhibition in HeLa-xenografted tumor model. The transcriptomic and proteomic analyses reveal the functional enrichment in the growth arrest, DDR and lysosomal pathways upon 20A treatment. More particularly, we find that ATM and autophagy are activated upon 20A treatment. Genetic inhibition of ATM following 20A treatment inhibits both autophagy and senescence and directs cells to apoptosis. Moreover, loss of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation and increased cell death triggered by 20A. Our results therefore identify ATM as a critical determinant in the balance between senescence and apoptosis and uncover autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal therapeutic effect of the 20A G4-ligand.

2019-04-17 | GSE113424 | GEO

Modulation of the ATM / autophagy pathway tips the balance between senescence and apoptosis in response to a quadruplex ligand

2019-02-19 | PXD009430 | Pride

Inhibition of Hedgehog Signaling Pathway Impairs Cancer Cell Growth via Promotion of Autophagy

Project description:Analysis of gene expression levels in response to inhibition of Hh signaling in ovarian and glioma cancer cells using a cDNA microarray technique. Microarray analyses revealed that differentially expressed genes (DEGs) in human cancer cells are enriched in the senescence and autophagy pathways in response to the inhibition of Hh signaling. Further investigations showed that inhibition of Hh signaling induced autophagy.. ES2 and H4 cells were treated with GANT61 (20 M-NM-<M for 32hr and 48hr) and control vehicle DMSO, respectively.

2014-06-15 | E-GEOD-54936 | biostudies-arrayexpress

MET Amplified Gastric Cancer Cell Lines +/- Crizotinib

Project description:MET amplification is present in 20% of gastric cancers and has been confirmed as a therapeutic target in clinical trials. The molecular mechanisms of response and resistance to MET inhibitors are not well understood. We investigated the determinants of MET dependency in human gastric cancer. MET inhibition inhibited proliferation and induced cell death only in MET-amplified gastric cancer cell lines. The effects on growth arrest were stronger than the effects on cell death. To identify possible resistance mechanisms, we performed whole-genome mRNA expression profiling. Molecular changes related to autophagy were among the top alterations observed. Consistent with these findings, autophagy levels increased in a concentration-dependent manner when MET-amplified cells were exposed to crizotinib. Autophagy inhibition caused a dramatic decrease in apoptosis in one of the MET-amplified cell lines (MKN45) but not in the other (SNU-5). Because autophagy may provide energy in cells subjected to growth factor deprivation, we explored the effects of MET or autophagy inhibition on cellular ATP levels. This revealed that autophagy-dependent ATP production was selectively required for apoptosis in the MKN45 cells and that chemical ATP depletion mimicked the effects of autophagy inhibition to block cell death. Overall, the data reveal a novel relationship between ATP depletion and resistance to MET inhibitor-induced cell death. Our observations suggest that autophagy inhibitors could have unintended consequences when they are combined with growth factor receptor inhibitors in tumors that require autophagy-dependent ATP production for apoptosis. 12 samples triplicate samples of SNU-5 and MKN45 +/- criztonib for 24 hours

2016-05-13 | E-GEOD-77320 | biostudies-arrayexpress

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1a (IL-1a) dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.

2022-02-08 | PXD030422 | Pride

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1 (IL-1 dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.

2022-02-08 | PXD020871 | Pride

RNA seq on NEO2734, CFI-400945 or SASP treated cells

Project description:Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies. However, lack of broadly acting senolytic drugs remains a challenge. Using inducible CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify here loss of the death receptor inhibitor cFLIP as a universal vulnerability of senescent cancer cells. Senescent cancer cells are primed for apoptotic death by NF-kB-mediated upregulation of death receptor DR5 and its ligand TRAIL but are protected from death by increased cFLIP. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of all senescent cancer cells tested. We validate this ?one-two punch? cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.

2022-08-24 | GSE191255 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data