Inhibition of Mnk–eIF4E Pathway Sensitizes The Efficacy to Chemotherapy in Anaplastic Thyroid Cancer

Hu, Kun; Zhang, Juan; Yu, Min; Xiong, Change

doi:10.2217/fon-2016-0320

Cited by 14 publications

(15 citation statements)

References 24 publications

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“…eIF4E activation has been shown to be cellular survival mechanisms in response to various stress conditions, such as chemotherapy, in various types of tumors . However, little is known on whether eIF4E activation is involved in HCC cells in response to chemotherapy.…”

Section: Resultsmentioning

confidence: 99%

Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin‐induced eIF4E activation

Tan

Song

et al. 2017

J Biochem & Molecular Tox

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Section: Resultsmentioning

confidence: 99%

Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin‐induced eIF4E activation

Tan

Song

et al. 2017

J Biochem & Molecular Tox

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“…Phosphorylation of EIF4E at Ser209 has been shown to be essential for EIF4E oncogenic activity. Earlier studies have shown that MNK kinase, downstream of MAPK pathway, can phosphorylate EIF4E at Ser209 (49, 50). Our results suggest that overexpression or inhibition of AURKA can affect the phosphorylation of EIF4E without changing MNK phosphorylation levels.…”

Section: Introductionmentioning

confidence: 99%

Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells

Katsha

Wang

Arras

et al. 2017

Clinical Cancer Research

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Purpose Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus). Experimental design Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGCs) were used to determine the role of AURKA in activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivo. Results Using in vitro cell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A (PP2A), a negative regulator of EIF4E, leading to activation of EIF4E and resistance to everolimus in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib. Conclusion Our results indicate that AURKA plays an important role in activation of EIF4E and cap-dependent translation. Targeting AURKA-EIF4E-c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus-resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4Eand c-MYC.

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“…MNKs activity in thyroid cancer has been mainly associated with drug resistance mechanisms. In thyroid cancer cell lines, an increase in MNK-dependent eIF4E phosphorylation is observed after DNA damage by cisplatin [154] or by radionuclide therapy with radiolabeled gastrin analogs [151] and after inhibition of BET proteins, which function as transcriptional co-activators of oncogenic genes [155]. MNK inhibition or knockdown blocks the increased eIF4E phosphorylation and enhances the antitumor effects of these therapies in vitro [151] and in vivo [154,155].…”

Section: Mnk In Other Solid Tumorsmentioning

confidence: 99%

“…In thyroid cancer cell lines, an increase in MNK-dependent eIF4E phosphorylation is observed after DNA damage by cisplatin [154] or by radionuclide therapy with radiolabeled gastrin analogs [151] and after inhibition of BET proteins, which function as transcriptional co-activators of oncogenic genes [155]. MNK inhibition or knockdown blocks the increased eIF4E phosphorylation and enhances the antitumor effects of these therapies in vitro [151] and in vivo [154,155]. In addition, MNK inhibition or genetic depletion alone inhibits proliferation and induces apoptosis of anaplastic thyroid cancer cells, the most aggressive type of thyroid cancer, and reduces tumor growth in a mouse xenograft model [154].…”

Section: Mnk In Other Solid Tumorsmentioning

confidence: 99%

“…MNK inhibition or knockdown blocks the increased eIF4E phosphorylation and enhances the antitumor effects of these therapies in vitro [151] and in vivo [154,155]. In addition, MNK inhibition or genetic depletion alone inhibits proliferation and induces apoptosis of anaplastic thyroid cancer cells, the most aggressive type of thyroid cancer, and reduces tumor growth in a mouse xenograft model [154].…”

Section: Mnk In Other Solid Tumorsmentioning

confidence: 99%

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Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

Pinto-Díez

Ferreras-Martín

Carrión-Marchante

et al. 2020

IJMS

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The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.

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Inhibition of Mnk–eIF4E Pathway Sensitizes The Efficacy to Chemotherapy in Anaplastic Thyroid Cancer

Abstract: Targeting Mnk-eIF4E pathway provides a therapeutic strategy by sensitizing ATC response to chemotherapeutic drug.

Cited by 14 publications

References 24 publications

Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin‐induced eIF4E activation

Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin‐induced eIF4E activation

Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

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