15357163mct140064-sup-125804_2_supp_2613249_n2c226.pptx (55.07 kB)
Supplementary Figure 7 from CBS9106-Induced CRM1 Degradation Is Mediated by Cullin Ring Ligase Activity and the Neddylation Pathway
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posted on 2023-04-03, 14:00 authored by Naoya Saito, Keiichi Sakakibara, Takuji Sato, Jonathan M. Friedman, Donald W. Kufe, Daniel D. VonHoff, Takumi KawabeSupplementary Figure 7: Schematic representation that summarizes the proposed mechanism of action of CBS9106.
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ARTICLE ABSTRACT
Chromosome region maintenance 1 (CRM1) mediates the nuclear export of proteins and mRNAs, and is overexpressed in various cancers. Recent studies have also reported that CRM1 protein expression is a negative prognostic factor in patients with cancer. Therefore, CRM1 is considered a potential target for anticancer therapy. Our previous study demonstrated that CBS9106, a synthetic small-molecular inhibitor of CRM1, decreases CRM1 protein through proteasomal degradation without affecting CRM1 mRNA levels. However, the mechanism by which CRM1 is degraded is not well understood. Here, we demonstrate a novel signaling pathway that plays an important role in CBS9106-induced CRM1 degradation. We found that MLN4924, a selective inhibitor of NEDD8-activating enzyme (NAE), effectively inhibits cullin neddylation and attenuates CBS9106-induced CRM1 degradation in a time- and dose-dependent manner. MLN4924 also attenuated CBS9106-induced nuclear accumulation of Ran-binding protein 1 (RanBP1), cell growth inhibition, and apoptosis. Furthermore, RNAi-mediated knockdown of neddylation pathway proteins (NEDD8 and UBA3) or cullin ring ligase (CRL) component protein (Rbx1) attenuated CRM1 protein degradation and G1 phase cell-cycle arrest by CBS9106. Knockdown of CSN5 or CAND1 also partially inhibited CBS9106-induced CRM1 degradation. These findings demonstrate that CBS9106-induced CRM1 degradation is conferred by CRL activity involving the neddylation pathway, and that this response to CBS9106 leads to cell growth inhibition and apoptosis. Mol Cancer Ther; 13(12); 3013–23. ©2014 AACR.Usage metrics
Keywords
Cell CycleCell cycle checkpointsDrug MechanismsDrug-mediated stimulation of cell death pathwaysp53 and anticancer drug actionDrug TargetsOncoprotein & tumor suppressor drug targetsGastrointestinal CancersColorectal cancerGenome BiologySilencing and reactivation of gene expressionOncogenes & Tumor SuppressorsSmall Molecule Agents
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