Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis

Zakaria, Chadi; Sean, Polen; Hoang, Huy-Dung; Leroux, Louis‐Philippe; Watson, Margaret; Workenhe, Samuel T.; Hearnden, Jaclyn; Pearl, Dana; Truong, Vinh Tai; Robichaud, Nathaniel; Yanagiya, Akiko; Tahmasebi, Soroush; Jafarnejad, Seyed Mehdi; Jia, Jianjun; Pelin, Adrian; Diallo, Jean-Simon; Bœuf, Fabrice Le; Bell, John C.; Mossman, Karen; Graber, Tyson E.; Jaramillo, Maritza; Sonenberg, Nahum; Alain, Tommy

doi:10.1371/journal.ppat.1007264

Cited by 23 publications

(23 citation statements)

References 58 publications

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“…Thus, targeting mTOR can contribute to explore novel therapeutic strategies of anticancer. The eIF signaling cascade is mainly regulated via the PI3K/AKT/mTOR pathway due to its vital role in regulating cell growth and proliferation [49,50]. Moreover,it is con rmed that eIF6 can positively regulate AKT-related cancer signaling and contribute to the malignant behavior of CRC [28].…”

Section: Discussionmentioning

confidence: 99%

eIF6 Promotes the Malignant Progression of Human Hepatocellular Carcinoma via the mTOR Signaling Pathway

Sun

Wang

Zheng³

et al. 2020

Preprint

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Background Eukaryotic translation initiation factor 6 (eIF6) has a crucial function in the maturation of 60S ribosomal subunits, and it controls the initiation of protein translation. Although emerging studies indicate that eIF6 is aberrantly expressed in various types of cancers, the functions and underlying molecular mechanisms of eIF6 in the pathological progression of hepatocellular carcinoma (HCC) remain unclear. This study aimed to evaluate the potential diagnostic and prognostic value of eIF6 in patients with HCC. Methods HCC samples enrolled from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and our cohort were used to explore the role and mechanism of eIF6 in HCC. The diagnostic power of eIF6 was verified by receiver operating characteristic curve (ROC) analysis and its prognostic value was assessed by Kaplan-Meier analysis, and then related biological functions of eIF6 were determined in vitro and in vivo cancer models. In addition, potential molecular mechanism of eIF6 in HCC was unveiled by the gene set enrichment analysis and western blot assay. Results We demonstrated that eIF6 expression was markedly increased in HCC, and elevated eIF6 expression correlated with pathological progression of HCC. Besides, eIF6 served as not only a new diagnostic biomarker but also an independent risk factor for OS in HCC patients. Functional studies indicated that the deletion of eIF6 displayed tumor-suppressor activity in HCC cells. Furthermore, we found that eIF6 could activate the mTOR-related signaling pathway and regulate the expression level of its target genes, such as CCND1, CDK4, CDK6, MYC, CASP3 and CTNNBL1, and these activities promoted proliferation and invasion of HCC cells. Conclusions The findings of this study provided a novel basis for understanding the potential role of eIF6 in promoting tumor growth and invasion, and exploited a promising strategy for improving diagnosis and prognosis of HCC.

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Section: Discussionmentioning

confidence: 99%

eIF6 Promotes the Malignant Progression of Human Hepatocellular Carcinoma via the mTOR Signaling Pathway

Sun

Wang

Zheng³

et al. 2020

Preprint

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“… 177 Recently, a new generation of mTOR inhibitor, ATP-competitive active-site mTORC1 and 2 inhibitors (asTORi) enhanced ICP0-deleted HSV1 infection specifically in transformed cells (such as human GBM cells) via inhibition of cellular type-I IFN responses, while reducing infection in non-transformed cells. 178 The promising outcome of this combination study warrants further pre-clinical research in vivo in GBM models and clinical translation in GBM patients.…”

Section: Ohsv-based Combination Therapies For Gbmmentioning

confidence: 92%

The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment

Nguyen¹,

Saha²

2021

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Glioblastoma (GBM) is a lethal primary malignant brain tumor with no current effective treatments. The recent emergence of immuno-virotherapy and FDA approval of T-VEC have generated a great expectation towards oncolytic herpes simplex viruses (oHSVs) as a promising treatment option for GBM. Since the generation and testing of the first genetically engineered oHSV in glioma in the early 1990s, oHSV-based therapies have shown a long way of great progress in terms of anti-GBM efficacy and safety, both preclinically and clinically. Here, we revisit the literature to understand the recent advancement of oHSV in the treatment of GBM. In addition, we discuss current obstacles to oHSV-based therapies and possible strategies to overcome these pitfalls.

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“…Bone marrow-derived macrophages (BMDMs) were generated from 6 to 8 week-old female C57BL/6 mice (Jackson Laboratory), as previously described (Leroux et al, 2018 ; Zakaria et al, 2018 ; Chaparro et al, 2020 ). Briefly, marrow was extracted from bones of the hind legs, red blood cells were lysed, and progenitor cells were resuspended in BMDM culture medium supplemented with 15% L929 fibroblast-conditioned culture medium (LCCM).…”

Section: Methodsmentioning

confidence: 99%

Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival

Leroux

Chaparro

Jaramillo

2020

Front. Cell. Infect. Microbiol.

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The obligate intracellular parasite Toxoplasma gondii reprograms host gene expression through multiple mechanisms that promote infection, including the up-regulation of mTOR-dependent host mRNA translation. In addition to the mTOR-4E-BP1/2 axis, MAPK-interacting kinases 1 and 2 (MNK1/2) control the activity of the mRNA cap-binding protein eIF4E. Herein, we show that T. gondii inhibits the phosphorylation of MNK1/2 and their downstream target eIF4E in murine and human macrophages. Exposure to soluble T. gondii antigens (STAg) failed to fully recapitulate this phenotype indicating the requirement of live infection. Treatment with okadaic acid, a potent phosphatase inhibitor, restored phosphorylation of MNK1/2 and eIF4E regardless of infection. T. gondii replication was higher in macrophages isolated from mice mutated at the residue where eIF4E is phosphorylated (eIF4E S209A knock-in) than in wild-type (WT) control cells despite no differences in infection rates. Similarly, parasitemia in the mesenteric lymph nodes and spleen, as well as brain cyst burden were significantly augmented in infected eIF4E S209A knock-in mice compared to their WT counterparts. Of note, mutant mice were more susceptible to acute toxoplasmosis and displayed exacerbated levels of IFNγ. In all, these data suggest that the MNK1/2-eIF4E axis is required to control T. gondii infection and that its inactivation represents a strategy exploited by the parasite to promote its survival.

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Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis

Cited by 23 publications

References 58 publications

eIF6 Promotes the Malignant Progression of Human Hepatocellular Carcinoma via the mTOR Signaling Pathway

eIF6 Promotes the Malignant Progression of Human Hepatocellular Carcinoma via the mTOR Signaling Pathway

The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment

Infection by the Protozoan Parasite Toxoplasma gondii Inhibits Host MNK1/2-eIF4E Axis to Promote Its Survival

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