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Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201.

ABSTRACT: RNA-Seq analysis of prostate cancer cells primed to irradiation for 24hours with ONC201 shows a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136975 | GEO | 2021/02/21

REPOSITORIES: GEO

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Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201.

Project description:Modulating the unfolded protein response: Impacts of radiation on the response of prostate cancer cells to ONC201.

| PRJNA564135 | ENA

Modulating the unfolded protein response with ONC201 to impact on radiation response in prostate cancer cells.

Project description:Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.

| S-EPMC7896060 | biostudies-literature

Patient-derived HK-374 glioblastoma cells treated with radiation and ONC201

Project description:RNASeq results for HK-374 treated with DMSO, radiation, ONC201 or radiation plus ONC201

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Effects of ONC201 on mantle cell lymphoma cell lines

Project description:The small molecule ONC201 is toxic in vitro to multiple cell lines and primary tumor samples of mantle cell lymphoma (MCL) and acute myeloid leukemia, even ones with unfavorable genetic features (notably including TP53 inactivation) or acquired resistance to other agents. Because the mechanism of action in these malignant hematologic cells appeared to differ from that in solid tumors, we performed gene expression profiling (GEP) studies on MCL lines treated with ONC201 and other agents with known mechanisms of action. Treatment of JeKo-1 cells with 5 uM ONC201 showed consistent and progressive increases or decreases over time in two sets of genes: upregulated genes, which implicated an ER stress response and mTOR pathway inhibition, and downregulated genes, which implicated reduced proliferation. These implicated effects of ONC201 were validated by confirmatory experiments. Similar GEP changes were observed in ONC201-naive Z138 cells after 24 hr of ONC201 treatment, but were not seen in Z138 cells made ONC201-resistant by chronic exposure. Finally, the GEP effects of ONC201 in JeKo-1 cells were mimicked by the ER stress inducer tunicamycin, but not by the direct MTOR inhibition rapamycin, further confirming an ER stress response and suggesting that inhibition of the mTOR pathway was by an indirect mechanism. For each experiment, cells from a single stock culture of each cell line used were aliquoted into individual culture plate wells, establishing individual replicates, and drugs were added to start the experiment. Treated replicates were harvested after the times of treatment indicated, by pelleting cells, lysing pellets in TriZOL, and freezing TriZOL until RNA isolation. Untreated replicates, serving as controls, were either harvested at the beginning of the experiment or at later times, as specified below.

2016-02-20 | E-GEOD-68091 | biostudies-arrayexpress

Effects of ONC201 on mantle cell lymphoma cell lines

2016-02-20 | GSE68091 | GEO

Anti-cancer agent ONC201 activates early ATF4/DR5 upregulation, and cell death associated with XIAP inhibition

Project description:Two experiments were performed with ONC201/TIC10 in human colon cancer cell lines. The first experiment is TIC10-induced transcriptional changes at 48hrs in HCT116 p53-null cells (10uM). The second experiment is RKO cells, with and without acquired resistance to ONC201, treated with with ONC201 (10uM) for 48 hrs. For the first experiment, six samples of HCT116 p53-null cells with TIC10 (10uM) or DMSO treatment. Three replicates each. For the second experiment, six samples of wild-type RKO cells with ONC201 (10uM) or DMSO treatment and the same treatments for RKO cells with acquired resistance to ONC201.

2016-06-01 | E-GEOD-72865 | biostudies-arrayexpress

Effect of TIC10/ONC201 on glioma cells

Project description:We performed microarray analysis in order to evaluate the effect of ONC201 on gene expression in glioma cells (U87).

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Anti-cancer agent ONC201 activates early ATF4/DR5 upregulation, and cell death associated with XIAP inhibition

2016-06-01 | GSE72865 | GEO

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.

2023-05-25 | PXD036245 | Pride

Effect of ONC201 and its derivatives (ONC206 and ONC212) on glioma cells

Project description:We performed microarray analysis in order to evaluate the effect of ONC201 and its derivatives (ONC206 and ONC212) on gene expression in U87 glioma cells.

2018-09-25 | GSE104273 | GEO

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