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Inhibition of HDAC1/2 along with TRAP1 causes Synthetic Lethality in Glioblastoma Model Systems

ABSTRACT: Pan and selective HDAC inhibition is synthetically lethal with TRAP1 inhibition in various model systems of glioblastoma, including patient derived xenograft (PDX) cells. Mechanistically, this occurs through several mechanisms, including the induction of metabolic stress by interference with tumor cell energy metabolism accompanied by modulation of pro- and anti-apoptotic Bcl-2 family proteins and the induction of a cell death with apoptotic features.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150395 | GEO | 2020/05/13

REPOSITORIES: GEO

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Inhibition of HDAC1/2 along with TRAP1 causes Synthetic Lethality in Glioblastoma Model Systems

Project description:Inhibition of HDAC1/2 along with TRAP1 causes Synthetic Lethality in Glioblastoma Model Systems

| PRJNA631973 | ENA

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems.

Project description:The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma.

| S-EPMC7407106 | biostudies-literature

Transgenic Expression Of Mitochondrial Chaperone Trap1 Accelerates Prostate Cancer Development

Project description:Protein homeostasis, or proteostasis is critical for organelle function, including mitochondria, but its role in cancer is controversial. Here, we show that transgenic mice expressing the mitochondrial chaperone, TRAP1 in the prostate develop prostatic hyperplasia and cellular atypia. When examined on a Pten+/- background, a common alteration in prostate cancer patients, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ. Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten+/- mice, without affecting hyperplasia or prostatic intraepithelial neoplasia (PIN). Global RNA sequencing and reverse phase protein array profiling of Pten+/--TRAP1 transgenic tumors reveals modulation of oncogenic networks of cell proliferation, apoptosis, cell motility, DNA damage and metabolism. Mechanistically, reconstitution of Pten+/- prostatic epithelial cells with TRAP1 results in increased cell proliferation, reduced apoptosis, heightened cell invasion, and no changes in mitochondrial bioenergetics. Therefore, TRAP1 promotes invasive prostate cancer, and provides an “actionable” therapeutic target in patients with advanced disease.

2017-05-11 | GSE81316 | GEO

TRAP1 silencing in HCT116 cells

Project description:Trascription profiling analysis was performed on HCT-116 cell lines transiently silenced with TRAP1 compared with scrumble

2014-11-15 | E-MTAB-2500 | biostudies-arrayexpress

TRAP1 gene silencing in MCF7 cell lines

Project description:Transcription profiling by array of MCF7 cell lines silenced with TRAP1 small interfering RNA compared with scramble

2017-06-30 | E-MTAB-3584 | biostudies-arrayexpress

Coordinated regulation of protein synthesis and mitochondrial respiration by the molecular chaperone TRAP1 in cancer cells

Project description:Here we show that TRAP1 directly binds translation elongation factors, both inside and outside mitochondria, and slows down translation. TRAP1 overexpression or silencing affects the synthesis of respiratory complex components. Inside mitochondria, TRAP1 binds the Complex III core component UQCRC2 and regulates Complex III activity. This decreases respiration rate upon basal condition but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which TRAP1-UQCRC2 binding is lost. In humans, TRAP1 is co-expressed with the mitochondrial translational machinery, which synthesize respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, in which mitochondrial and cytosolic protein synthesis are co-regulated with energetic metabolism through the contribution of a common molecular chaperone

2023-12-07 | GSE141616 | GEO

Project description:TRAP1 is a HSP90 molecular chaperone involved in cancer cell adaptation to unfavorable environments and metabolic reprogramming. The role of TRAP1 in the adaptive response to hypoxia was investigated in human colorectal cancer.

2022-05-30 | E-MTAB-10563 | biostudies-arrayexpress

Mutation in mitochondrial chaperone TRAP1 is responsible for male-specific autism

Project description:There is growing evidence of mitochondrial disturbance in autism spectrum disorders (ASD) but causative relations remain to be established. We identified postzygotic mozaicp.Q639* mutation in the TRAP1 gene encoding mitochondrial chaperone of the HSP90 family in ASD patient whose monozygotic twin brother was healthy. An additional survey of 176 unrelated ASD probands showed identical TRAP1 variant in a single male patient. We generated a knock-in Trap1 p.Q641*mouse which displayed behavioral abnormalities relevant for ASD, that were more pronounced in males. This effect was corroborated by gender-specific differences in synaptic plasticity and the density of synaptic mitochondria. Next we performed transcriptome profiling by sequencing of RNA isolated from hippocampi of WT, HET and MUT male and female mice

2024-03-01 | GSE226319 | GEO

RNA-Sequencing analysis of BET inhibitor resistant cell lines

Project description:Targeting BET bromodomain proteins utilizing small molecules in an emerging anti-cancer strategy with clinical evaluation of at least six inhibitors now underway. While MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional anti-tumor activities are important. Using the Eμ-Myc model of B-cell lymphoma we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of pro-apoptotic (Bim) and anti-apoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eμ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1-resistance phenotype. These studies provide important information on mechanisms apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas.

2016-09-18 | GSE87050 | GEO

BCL-XL inhibition induces an FGFR4 mediated rescue response in colorectal cancer

Project description:The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3-mimetics can induce apoptosis. To identify pathways that can regulate sensitivity to BCL-XL inhibition, we screened a compound library for synergy with low dose BCL-XL inhibitor A-1155463 and reveal that FGFR4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.

2021-12-22 | GSE159504 | GEO

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