CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway

Wen, Qiuyuan; Wang, Weiyuan; Luo, Jianmin; Chu, Shuzhou; Chen, Lingjiao; Xu, Lina; Zang, Hongjing; Alnemah, Mohannad Ma; Ma, Jian; Fan, Songqing

doi:10.18632/oncotarget.8497

Cited by 51 publications

(50 citation statements)

References 44 publications

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“…We exposed a range of NPC cell lines and immortalized normal nasopharyngeal epithelial cell line to CGP57380 and observed that targeting the MNK-eIF4E axis by CGP57380 treatment decreased their proliferation and colony-forming ability with little apparent toxicity to the immortalized normal nasopharyngeal epithelial cell line, which was consistent with previous investigations in blast crisis chronic myeloid leukemia and NSCLC 18, 51. Paradoxically, when expression of p-MNK1 and p-eIF4E was inhibited by CGP57380, the expression of total β-catenin was stimulated but the downstream targets of β-catenin signaling, including cyclin D1, c-Myc, MMP-7, and Axin2, were suppressed in a time- and dose-dependent manner.…”

Section: Discussionsupporting

confidence: 86%

Suppression Of β-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma

Wang¹,

Wen²,

Luo³

et al. 2017

Theranostics

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Nuclear localization of β-catenin is essential for the progression of various human cancers via transcriptional upregulation of downstream genes. The MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis has been reported to activate Wnt/β-catenin signaling, and CGP57380, an inhibitor of MNK kinases, inhibits the proliferation of multiple cancers. In this study, we showed that β-catenin signaling (including β-catenin, cyclin D1, c-Myc, and MMP-7) and p-eIF4E expression were elevated in nasopharyngeal carcinoma (NPC) compared with non-cancerous nasopharyngeal epithelial tissues, and was associated with clinical characteristics of NPC patients. Lymph node metastasis, gender, aberrant β-catenin expression, and elevated levels of MMP-7 and cyclin D1 were independent prognostic factors. Significantly, expression of p-eIF4E was positively correlated with β-catenin, and targeting the MNK-eIF4E axis with CGP57380 downregulated β-catenin in the nucleus, which in turn decreased proliferation, cell cycle progression, migration, invasion, and metastasis of NPC in vitro and in vivo. CGP57380 also potentiated radiation-induced apoptosis in NPC. Moreover, CGP57380 upregulated β-catenin in the cytoplasm thus blocking epithelial-mesenchymal transition (EMT), a key mechanism in cancer cell invasiveness and metastasis. Mechanistically, inhibition of β-catenin nuclear translocation by CGP57380 was dependent on AKT activation. Notably, identification of the MNK/eIF4E/β-catenin axis might provide a potential target for overcoming the poor prognosis mediated by β-catenin in NPC.

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Section: Discussionsupporting

confidence: 86%

Suppression Of β-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma

Wang¹,

Wen²,

Luo³

et al. 2017

Theranostics

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“…A recent study also found that the MNK inhibitor, CGP57380, attenuates RAD001-activated eIF4E phosphorylation in non-small-cell lung cancer cells. Such a combination of inhibitors augmented the antitumor response by inhibiting cell proliferation and inducing apoptosis [98].…”

Section: Interplay Between the Mtor And Mnk/eif4e Pathwaysmentioning

confidence: 99%

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

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“…The aberrant expression of mTor has been shown to be essential for the tumorigenesis of the majority of all cancers [8–11], including OS [12]. Recently, the membrane-associated E3 ubiquitin ligase ZNRF2 has been shown to be involved in the activation and regulation of mTor through protein interaction [13].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-100 suppresses human osteosarcoma cell proliferation and chemo-resistance via ZNRF2

Xiao

et al. 2017

Oncotarget

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Osteosarcoma (OS) is a prevalent cancer worldwide. MicroRNAs (miRNAs) play critical roles in the growth, invasion and carcinogenesis of OS, whereas the underlying mechanisms remain ill-defined. Here, we addressed these questions. We detected significantly higher levels of ZNRF2, a ubiquitin ligase of the RING superfamily, and significantly lower levels of miR-100 in the OS specimens, compared to the paired normal bone tissues. The levels of ZNRF2 and miR-100 inversely correlated in the OS specimens. In addition, low miR-100 levels are associated with poor prognosis of the OS patients. Either ZNRF2 overexpression or miR-100 depletion increased in vitro OS cell growth and improved cell survival at the presence of Doxorubicin. Mechanistically, with the help of bioinformatics analysis and luciferase-reporter assay, we found that miR-100 might bind to the 3’-UTR of ZNRF2 mRNA to prevent its protein translation. Thus, our data suggest that re-expression of miR-100 may inhibit OS cell growth and decrease OS cell chemo-resistance.

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CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway

Cited by 51 publications

References 44 publications

Suppression Of β-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma

Suppression Of β-catenin Nuclear Translocation By CGP57380 Decelerates Poor Progression And Potentiates Radiation-Induced Apoptosis in Nasopharyngeal Carcinoma

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

MicroRNA-100 suppresses human osteosarcoma cell proliferation and chemo-resistance via ZNRF2

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