Targeting translation: eIF4E as an emerging anticancer drug target

Lu, Chunwan; Makala, Levi; Wu, Daqing; Cai, Yuanqiang

doi:10.1017/erm.2015.20

Cited by 43 publications

(59 citation statements)

References 146 publications

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“…6A). In addition, eIF4E was considered to play a rate-limiting role in driving translation of VEGF [30]. Intriguingly, western blot analysis manifested that the phosphorylation of eIF4E in response to irradiation was inhibited when caspase 3 was inactivated (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism

Xiao

et al. 2017

Cancer Letters

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Vascular recovery or re-angiogenesis after radiotherapy plays a significant role in tumor recurrence, whereas molecular mechanisms of this process remain elusive. In this work, we found that dying glioma cells promoted post-irradiation angiogenesis through a caspase 3 dependent mechanism. Evidence in vitro and in vivo indicated that caspase 3 inhibition undermined proangiogenic effects of dying glioma cells. Proteolytic inactivation of caspase 3 in glioma cells reduced tumorigenicity. Importantly, we identified that NF-κB/COX-2/PGE2 axis acted as downstream signaling of caspase 3, mediating proangiogenic response after irradiation. Additionally, VEGF-A, regulated by caspase 3 possibly through phosphorylated eIF4E, was recognized as another downstream factor participating in the proangiogenic response. In conclusion, these data demonstrated that caspase 3 in dying glioma cells supported the proangiogenic response after irradiation by governing NF-κB/COX-2/PGE2 axis and p-eIF4E/VEGF-A signaling. While inducing caspase 3 activation has been a generally-adopted notion in cancer therapeutics, our study counterintuitively illustrated that caspase 3 activation in dying glioma cells unfavorably supported post-irradiation angiogenesis, suggesting that radiotherapy combined with caspase 3 inhibitors may be more effective strategies due to restricted post-irradiation angiogenesis.

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Section: Resultsmentioning

confidence: 99%

Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism

Xiao

et al. 2017

Cancer Letters

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“…These inhibitors simultaneously target ATP binding sites of mTORC and PI3K with similar potency, and include SF1126, NVP-BEZ235, NVP-BGT226, PI103, XL765, and GNE-477 [59–61, 97–99]. These compounds can prevent PI3K pathway reactivation caused by the mTOR–p70S6K negative feedback loop, and thus have the potential to more thoroughly sequester eIF4E [58]. In contrast to conventional mTOR inhibitors, a novel esterified KβBA derivative, cinnamoyl-KβBA (C-KβBA), is reported to inhibit mTOR activity via downregulating the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTORC1.…”

Section: Therapeutic Targeting Of Cap-dependent Translational Complexmentioning

confidence: 99%

“…MNK degraders comprise of novel retinamides, galeterone (gal), and gal analogs (e.g., VNPT55) which have shown promise in inhibiting eIF4E activation and tumor growth in prostate, breast and pancreatic cancers [33,64–67]. MNK inhibitors, including CGP052088, CGP57380, cercosporamide, and 5-(2-(phenyloamino)pyrymidin-4-yl)thiazole-2(3H)-one derivatives, have also been well studied [58]. The first preclinical proof of concept for novel MNK degrading agents (novel retinamides) was reported by our group [64].…”

Section: Therapeutic Targeting Of Cap-dependent Translational Complexmentioning

confidence: 99%

Targeting of protein translation as a new treatment paradigm for prostate cancer

Ramamurthy¹,

Ramalingam²,

Kwegyir-Afful³

et al. 2017

Current Opinion in Oncology

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Purpose of review This overview will summarize some of the developments in the area of protein translation, including as they relate to the therapeutic targeting of prostate cancer. Recent findings Translational control, mediated by the rate-limiting eukaryotic translation initiation factor 4E (eIF4E), drives selective translation of several oncogenic proteins, thereby contributing to tumor growth, metastasis, and treatment resistance in various cancers, including prostate cancer. As an essential regulatory hub, several oncogenic hyperactive signaling pathways appear to converge on eIF4E to promote tumorigenesis. Several approaches that target the eIF4E-dependent protein translation network are being actively studied, and it is likely that some may ultimately emerge as promising anticancer therapeutics. Summary An array of inhibitors has shown promise in targeting specific components of the translational machinery in several pre-clinical models of prostate cancer. It is hoped that some of these approaches may ultimately have relevance in improving the clinical outcomes of patients with advanced prostate cancer.

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“…eIF4E overexpression has been identified in 30% of human cancers generally,97,106–110 including in invasive breast cancer where the degree of eIF4E, both gene and protein overexpression, has been positively correlated with occurrence, recurrence, and metastasis 111–118. eIF4E protein expression was associated with shorter survival, higher tumor mitotic index, and higher-grade breast cancer 115.…”

Section: Drugs To Inhibit Emtmentioning

confidence: 99%

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

Kast¹,

Skuli

Cos

et al. 2017

BCTT

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Breast cancer metastatic to bone has a poor prognosis despite recent advances in our understanding of the biology of both bone and breast cancer. This article presents a new approach, the ABC7 regimen (Adjuvant for Breast Cancer treatment using seven repurposed drugs), to metastatic breast cancer. ABC7 aims to defeat aspects of epithelial-to-mesenchymal transition (EMT) that lead to dissemination of breast cancer to bone. As add-on to current standard treatment with capecitabine, ABC7 uses ancillary attributes of seven already-marketed noncancer treatment drugs to stop both the natural EMT process inherent to breast cancer and the added EMT occurring as a response to current treatment modalities. Chemotherapy, radiation, and surgery provoke EMT in cancer generally and in breast cancer specifically. ABC7 uses standard doses of capecitabine as used in treating breast cancer today. In addition, ABC7 uses 1) an older psychiatric drug, quetiapine, to block RANK signaling; 2) pirfenidone, an anti-fibrosis drug to block TGF-beta signaling; 3) rifabutin, an antibiotic to block beta-catenin signaling; 4) metformin, a first-line antidiabetic drug to stimulate AMPK and inhibit mammalian target of rapamycin, (mTOR); 5) propranolol, a beta-blocker to block beta-adrenergic signaling; 6) agomelatine, a melatonergic antidepressant to stimulate M1 and M2 melatonergic receptors; and 7) ribavirin, an antiviral drug to prevent eIF4E phosphorylation. All these block the signaling pathways – RANK, TGF-beta, mTOR, beta-adrenergic receptors, and phosphorylated eIF4E – that have been shown to trigger EMT and enhance breast cancer growth and so are worthwhile targets to inhibit. Agonism at MT1 and MT2 melatonergic receptors has been shown to inhibit both breast cancer EMT and growth. This ensemble was designed to be safe and augment capecitabine efficacy. Given the expected outcome of metastatic breast cancer as it stands today, ABC7 warrants a cautious trial.

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Targeting translation: eIF4E as an emerging anticancer drug target

Cited by 43 publications

References 146 publications

Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism

Dying glioma cells establish a proangiogenic microenvironment through a caspase 3 dependent mechanism

Targeting of protein translation as a new treatment paradigm for prostate cancer

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

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