Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA251414 | ENA |
REPOSITORIES: ENA
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Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.
2009-02-20 | GSE14003 | GEO
Project description:The ubiquitin-proteasome system (UPS) has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks ER-associated protein degradation (ERAD), has anti-tumor and biologic activities similar to bortezomib, and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the upregulation of the BH3 only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes: First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anti-cancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death. Experiment Overall Design: 1. EerI 10 vs 0 Experiment Overall Design: 2. EerI 10 vs 0 Experiment Overall Design: 3. Bzm 10 vs 0 Experiment Overall Design: 4. Bzm 10 vs 0
2009-02-28 | E-GEOD-14003 | biostudies-arrayexpress
Project description:Bortezomib resistance in Mantle Cell Lymphoma (MCL) is associated with plasmacytic differentiation
| PRJNA124459 | ENA
Project description:Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. The biological basis for differences in response to BZM is not completely understood. Our previous work demonstrated marked differences in methylation between primary MCL and normal B cells. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. We examined genome-wide DNA methylation profiles in MCL patient treated with BZM using a NimbleGen array platform. DNA methylation analysis revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. Noxa depletion by RNA interference protected MCL cells from death by these agents. These findings suggest a role for dynamic Noxa methylation for therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients. Our data demonstrate that genomic methylation profiling can provide mechanistic insights to guide novel therapeutic approaches.
2017-02-09 | GSE58165 | GEO
Project description:Drug-tolerant “persister” tumor cells underlie the emergence of drug-resistant clones contribute to relapse and disease progression; thus, identifying actionable targets that disable persisters and mitigate relapse are a high priority need. Although the BCL2-targeting agent venetoclax (ABT-199) has shown promising responses in mantle cell and double hit B cell lymphomas, resistance often arises, yet mechanistically how this occurs is unclear. Here we report that ABT-199 resistance can evolve from persister clones that have selective deletions at 18q21 that involve the drug target BCL2 and the apoptotic regulators Noxa (PMAIP1) and TCF4. Notably, reprogramming of super enhancers (SE) in persisters contributes to resistance, where there is a selection for SE-directed overexpression of the apoptotic regulator BCL2A1 and oncogenic transcription factors IKZF1 and FOXC1. At the same time, the SE reprogramming confers an opportunity for overcoming ABT-199 resistance. An unbiased drug screen on a platform that recapitulates the lymphoma microenvironment revealed that persisters are vulnerable to inhibitors of transcription initiation and elongation, and especially so to inhibitors of cyclin-dependent kinase 7 (CDK7) that is essential for transcription initiation. Specifically, CDK7 loss or inhibition eliminated the persister phenotype by disabling SE-driven expression of BCL2A1, IKZF1 and FOXC1. Thus, the co-treatment of ABT-199 with CDK7 inhibitors blocked the evolution of drug resistance, and provoked tumor regression in models of mantle cell lymphoma (MCL) and double hit lymphomas (DHL) that overexpress both MYC and BCL2. Together, these findings establish loss of apoptotic regulators and an adaptive transcriptional response as drug resistance mechanisms in lymphoma, more importantly, establish a rationale for transcription inhibition-based combination strategies to prevent and overcome drug resistance in B cell malignancies toward BCL2 inhibitor.
2020-05-26 | PXD010193 | Pride
Project description:TUBE and GST enrichment followed by 1D-gel-LC-MS analysis on cell exract from bortezomib (BTZ)-resistant or sensitive mantle cell lymphoma cells.
2022-02-28 | PXD011867 | Pride
Project description:Microenvironment-dependent proliferation and mitochondrial priming loss in mantle cell lymphoma is overcome by anti-CD20
| PRJNA341450 | ENA
Project description:Targeting DNMT3A-mediated oxidative phosphorylation to overcome ibrutinib resistance in mantle cell lymphoma
| PRJNA947608 | ENA