Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7β-Aurora A pathway

Duhamel, Stéphanie; Girondel, Charlotte; Dorn, Jonas F.; Tanguay, Pierre Luc; Voisin, Laure; Smits, Ron; Maddox, Paul S.; Meloche, Sylvain

doi:10.1080/15384101.2016.1183851

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…oxidative stress [ 38 ]. Also a hyperactivation of ERK1/2 is reported to promote aneuploidy by polyploidization [ 39 ]. However, the mechanisms how the absence of the eEF2 kinase impairs this pathway remain unclear and have to be subject of future studies.…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

et al. 2017

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Hepatocellular carcinoma is a cancer with increasing incidence and largely refractory to current anticancer drugs. Since Sorafenib, a multikinase inhibitor has shown modest efficacy in advanced hepatocellular carcinoma additional treatments are highly needed. Protein phosphorylation via kinases is an important post-translational modification to regulate cell homeostasis including proliferation and apoptosis. Therefore kinases are valuable targets in cancer therapy. To this end we performed 2D differential gel electrophoresis and mass spectrometry analysis of phosphoprotein-enriched lysates of tumor and corresponding non-tumorous liver samples to detect differentially abundant phosphoproteins to screen for novel kinases as potential drug targets. We identified 34 differentially abundant proteins in phosphoprotein enriched lysates. Expression and distribution of the candidate protein eEF2 and its phosphorylated isoform was validated immunohistochemically on 78 hepatocellular carcinoma and non-tumorous tissue samples. Validation showed that total eEF2 and phosphorylated eEF2 at threonine 56 are prognostic markers for overall survival of HCC-patients. The activity of the regulating eEF2 kinase, compared between tumor and non-tumorous tissue lysates by in vitro kinase assays, is more than four times higher in tumor tissues. Functional analyzes regarding eEF2 kinase were performed in JHH5 cells with CRISPR/Cas9 mediated eEF2 kinase knock out. Proliferation and growth is decreased in eEF2 kinase knock out cells.ConclusioneEF2 and phosphorylated eEF2 are prognostic markers for survival of hepatocellular carcinoma patients and the regulating eEF2 kinase is a potential drug target for tumor therapy.

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Section: Discussionmentioning

confidence: 99%

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

et al. 2017

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“…The excessive activation of the oncogenic ERK1/2 MAP kinase (MAPK) pathway results in the downregulation of FBXW7β both in epithelial cell lines and in the intestine tissue of a transgenic mouse model, conferring the stabilization of Aurora-A, abnormal cell division, and polyploidization. Consequently, the ERK1/2/FBXW7/Aurora-A axis is associated with aneuploidy and epithelial malignancies, and the MAPK can be a good candidate for target therapy in the not-too-distant future ( 170 ). Under the governance of p53-dependent transcription regulation, FBXW7 protects epithelial cells from DNA damage and malignant progression presumably through its substrate such as cyclin E, Aurora A, or c-MYC, and p53 heterozygosity combined with FBXW7 loss can confer aneuploidy as well as epithelial cancers ( 171 ).…”

Section: Fbxw7 and The Hallmarks Of Cancermentioning

confidence: 99%

FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

et al. 2022

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FBXW7, a member of the F-box protein family within the ubiquitin–proteasome system, performs an indispensable role in orchestrating cellular processes through ubiquitination and degradation of its substrates, such as c-MYC, mTOR, MCL-1, Notch, and cyclin E. Mainly functioning as a tumor suppressor, inactivation of FBXW7 induces the aberrations of its downstream pathway, resulting in the occurrence of diseases especially tumorigenesis. Here, we decipher the relationship between FBXW7 and the hallmarks of cancer and discuss the underlying mechanisms. Considering the interplay of cancer hallmarks, we propose several prospective strategies for circumventing the deficits of therapeutic resistance and complete cure of cancer patients.

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“…Based on an in vitro TR CRC cell model, we demonstrated that Fbxw7 was significantly downregulated in HCT-116 TR cells, suggesting that enhancing the Fbxw7 signaling pathway could contribute to overcoming Taxol resistance. Fbxw7 functions as a tumor suppressor and is negatively associated with tumor progression through targeting a cluster of oncoproteins, such as c-Myc (16), cyclin E (16), mTOR (17), and Aurora A (18). Despite the fact that diverse Fbxw7 substrates have been validated, novel oncoproteins of potential Fbxw7 targets and the molecular mechanisms underlying the functions of Fbxw7 in chemosensitivity remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Attenuating glucose metabolism by Fbxw7 promotes Taxol sensitivity of colon cancer cells through downregulating NADPH oxidase 1 (Nox1)

Wang¹,

Chen²,

Shen³

et al. 2021

Ann Transl Med

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Background: Colorectal cancer (CRC), one of the most common malignancies worldwide, is associated with poor survival and has a high mortality rate. Taxol is a chemotherapeutic agent that has been clinically applied as a first-line drug against diverse cancers. Yet, development of drug resistance has become the major challenge for anti-cancer treatments. F-box and WD40 domain protein 7 (Fbxw7) is a known tumor suppressor which is frequently downregulated in cancers. However, the biological roles and mechanisms of Fbxw7 in Taxol resistance are still under investigation.Methods: We report that Fbxw7 is significantly inactivated in CRC tumors and cell lines compared with normal tissues and colon cells. Expressions of Fbxw7 and Nox1 were detected from human colon tumors and cells by qRT-PCR and Western blot. Glycolysis rate was assessed by glucose uptake and lactate product assay. Interactions between Fbxw7 and Nox1 were determined by co-immunoprecipitation (Co-IP).Chemosensitivity and resistance of colon cancer cells were determined by MTT assay and Annexin V-FITC assay.Results: Overexpression of Fbxw7 sensitized colon cancer cells to Taxol. Moreover, we observed a negative correlation between Fbxw7 and glucose metabolism. From the established Taxol-resistant (TR) cell line from HCT-116, Fbxw7 was found to be markedly downregulated in HCT-116 TR cells. We detected that NADPH oxidase 1 (Nox1), a superoxide-generating NADPH oxidase, is negatively regulated by Fbxw7. The Co-IP assay showed that Fbxw7 interacted with Nox1, which was observed to be significantly upregulated in CRC tissues. Nox1 therefore promotes the Taxol resistance and glucose metabolism of colon cancer cells.Finally, rescue experiments demonstrated that the Fbxw7-promoted Taxol sensitivity was partially through the Nox1-glycolysis axis. Restoration of Nox1 in Fbxw7-overexpressed TR colon cancer cells significantly recovered the Taxol resistance, which could be further overridden by glycolysis inhibition.Conclusions: Collectively, this study uncovered that targeting the Fbxw7-Nox1-glucose metabolism axis could be an effective strategy against chemoresistant colon cancer.

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Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7β-Aurora A pathway

Cited by 5 publications

References 47 publications

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

Eukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC

FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies

Attenuating glucose metabolism by Fbxw7 promotes Taxol sensitivity of colon cancer cells through downregulating NADPH oxidase 1 (Nox1)

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