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XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

ABSTRACT: XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

PROVIDER: PRJNA688482 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13324109.fastq.gz	Fastqsanger.gz
	SRR13324110.fastq.gz	Fastqsanger.gz
	SRR13324111.fastq.gz	Fastqsanger.gz
	SRR13324112.fastq.gz	Fastqsanger.gz
	SRR13324113.fastq.gz	Fastqsanger.gz

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XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

Project description:The five-year survival rate remains less than 50% for high-risk neuroblastoma patients, few of them show effective response to current chemotherapy drugs. It is urgent to identify new therapeutic targets and corresponding drugs for high-risk neuroblastoma. Exportin-1(XPO1), also known as chromosomal region maintenance 1 (CRM1), plays important roles in the progress of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported. Here, our results showed that overexpression of XPO1 was significantly associated with poor clinical characteristics and prognosis of neuroblastoma patients. The specific inhibitor of XPO1 suppressed neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed neuroblastoma cells proliferation and induced cell apoptosis by FOXO1 and RB1 nuclear accumulation in neuroblastoma through inhibiting PI3K/AKT pathway, and induced G0/G1 phase cell arrest by activating P53 function. Together, XPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment by selective inhibitor verdinexor (KPT-335).

2021-08-18 | GSE163987 | GEO

XPO1 blockade with KPT-330 promotes apoptosis in Cutaneous T- cell Lymphoma by activating the p53-p21 and p27 pathways

Project description:To assess the effects of XPO1 inhibition with small molecule inhibitor KPT-330 on Cutaneous T-cell Lymphoma after 48 hours of treatment

2024-04-23 | GSE262491 | GEO

CRM1 inhibitor anti-tumor activity is enhanced with salicylates by S-phase arrest and impaired DNA-damage repair

Project description:Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (Selinexor), a CRM1 inhibitor approved for myeloma, has been limited by toxicity. We found that combining choline salicylate (CS) with low-doses of KPT-330 (K+CS) had potent synergistic activity across blood and solid organ cancers ex-vivo and in-vivo. Mechanistically, K+CS enhances CRM1 degradation, induces potent inhibition of CRM1 mediated nuclear export, and arrests cells in S-phase with simultaneous reduction of Rad51 causing impaired DNA damage repair. K+CS represents a potential new class of therapy for multiple cancer types.

2020-10-28 | GSE160186 | GEO

ChEC-seq2 profiling of Crm1 and Nup2 during degradation of Nup2 or inhibition/degradation of Crm1, respectively

Project description:Nuclear pore proteins (Nups) physically interact with hundreds of chromosomal sites, impacting transcription. In yeast, transcription factors mediate interactions between Nups and enhancers and promoters. To define the molecular basis of this mechanism, we exploited a separation-of-function mutation in the Gcn4 transcription factor that blocks its interaction with the nuclear pore complex (NPC). This mutation reduces the interaction of Gcn4 with the highly conserved nuclear export factor Crm1/Xpo1. Crm1 and Nups co-occupy enhancers and Crm1 inhibition blocks interaction of the nuclear pore protein Nup2 with the genome. In vivo, Crm1 interacts stably with the NPC. In vitro, Crm1 binds both Gcn4 and Nup2 directly. Importantly, the interaction between Crm1 and Gcn4 requires neither Ran-GTP nor the nuclear export sequence binding site. Finally, Crm1 and Ran-GTP stimulate DNA binding by Gcn4, suggesting that allosteric coupling between Crm1-Ran-GTP binding and DNA binding facilitates docking of transcription factor-bound enhancers at the NPC.

2025-03-24 | GSE288549 | GEO

Analysis of gene expression changes in KPT-185-treated HMLE cells transduced to stably overexpress SNAI1

Project description:HMLE-SNAIL cell cultures were treated with KPT-185 drug (KPT, 150 nanomolar) or vehicle (DMSO) for 24 hours, in parallel quadruplicates. KPT-185 is an Exportin 1 (XPO1) inhibitor with possible pluripotent or unexpected effects on cell signaling. Total RNA was isolated and analyzed in an Agilent two-color experiment, where four biological replicates of each condition were directly compared, expression ratios are KPT-treated condition relative to control (DMSO vehicle-treated).

2015-08-31 | GSE69326 | GEO

ChEC-seq2 profiling of yeast Gcn4 and Crm1-T539C localization after treatment with Leptomycin B.

2025-03-24 | GSE288550 | GEO

The XPO1 inhibitor KPT-8602 synergizes with dexamethasone for the inhibition of acute lymphoblastic leukemia

Project description:Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Survival of ALL patients has improved significantly over the last 50 years. However, the current intensified chemotherapy is associated with serious short and long-term side effects in these young patients. Whereas KPT-8602 is a second generation exportin-1 (XPO-1) inhibitor with potent activity against ALL in pre-clinical models and with minimal effects on normal cells. In this study, we evaluated if synergistic ALL inhibition could be obtained by combining KPT-8602 with dexamethasone, vincristine or doxorubicin. Combination of KPT-8602 with dexamethasone showed the strongest synergistic effect on human B-ALL and T-ALL cell lines. This synergy was confirmed in vivo on three patient-derived ALL xenografts. Compared to single drug treatment, the drug combination caused increased apoptosis, reduced cell cycle gene expression and led to histone depletion. mRNA expression analysis and ChIP-seq revealed that addition of KPT-8602 to dexamethasone increased transcript level and binding of the glucocorticoid receptor, as well as NFKBIA expression. Dexamethasone concentrations could be reduced 5 to 10-fold in the presence of KPT-8602 to achieve the same level of NFKBIA induction as with dexamethasone alone. Our pre-clinical study demonstrates that combination of KPT-8602 and dexamethasone is highly synergistic in vivo. This opens the possibility to reduce dexamethasone concentrations and reduce side effects in future clinical trials.

2019-08-05 | GSE135350 | GEO

ChEC-seq2 profiling of Crm1, Nucleoporins (nups), and RNA Pol II from budding yeast grown in SDC

2025-03-24 | GSE288515 | GEO

thiol(SH)-linked alkylation for the metabolic sequencing (SLAM-seq) of RNA after Crm1 inhibition and Nup1/Nup2 degradation

2025-03-24 | GSE288633 | GEO

XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor.

Project description:BackgroundHigh-risk neuroblastoma patients have a 5-year survival rate of less than 50%. It's an urgent need to identify new therapeutic targets and the appropriate drugs. Exportin-1 (XPO1), also known as chromosomal region maintenance 1, plays important roles in the progression of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported.MethodsCorrelations between XPO1 expression level and clinical characteristics were analyzed using the Neuroblastoma Research Consortium (NRC) dataset and tissue microarray analysis. Cell proliferation assays, colony formation assays, apoptosis assays, cell cycle analysis were performed to analyze the anti-tumor effects of verdinexor (KPT-335) in vitro. Western blot and mRNA sequencing were performed to explore underlying mechanism. In vivo anti-tumor effects of verdinexor were studied in a neuroblastoma xenograft model.ResultsHigher XPO1 levels were associated with advanced stage and poor prognosis in neuroblastoma patients. The specific inhibitor of XPO1 verdinexor suppressed the neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed the neuroblastoma cell proliferation and induced cell apoptosis by nuclear accumulation of FOXO1 and RB1 in the neuroblastoma due to the inhibition of the PI3K/AKT pathway, and induced G0/G1 phase cell cycle arrest by activation of P53 function.ConclusionsXPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment with selective inhibitor verdinexor.

| S-EPMC8359549 | biostudies-literature

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