Overexpression of eukaryotic initiation factor 4E (eIF4E) and its clinical significance in lung adenocarcinoma

Wang, Rui; Geng, Jian Guo; Wang, Jinghua; Chen, Xiaoyuan; Geng, Hui; Chen, Longbang

doi:10.1016/j.lungcan.2009.02.001

Cited by 50 publications

(40 citation statements)

References 25 publications

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“…These findings concur with those of Liu et al (21) and advocate that the activation of mTOR and p70S6K appears more critical during the early stages of lung carcinogenesis as opposed to 4E-BP1 and AKT, which is a rather late event, contributing to the acquisition of a more aggressive phenotype. In harmony with our results, eIF4E overexpression was reportedly more prevalent in advanced stages of lung adenocarcinomas (25), whereas published data regarding the association of p-AKT and stage are controversial (20,26). PTEN loss also marginally prevailed in high-grade cases, as in the study of Tang et al (20) and more importantly, the presence of the PTEN mutant genotype was associated with nodal metastases.…”

Section: Discussionsupporting

confidence: 89%

“…The strongest evidence supporting the role of the 4E-BP1/p-eIF4E interaction in NSCLC patient survival comes from 3 independent studies assigning a poor survival probability to p-eIF4E overexpression (18,24,25) in lung adenocarcinomas. Current belief holds that the activation of 4E-BP1 represents the convergence point of several oncogenic pathways apart form mTOR, hence providing a better reflection of tumour aggressiveness than the upstream genetic alterations (51).…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of this experimental evidence, it is not surprising that much effort has been devoted to the investigation of the expression profiles of various components of the PI3K/AKT/ mTOR pathway in NSCLC (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), sometimes yielding inconsistent results. In particular, a comprehensive analysis of all components of this pathway, along with the PIK3CA, K-RAS, AKT1 and PTEN mutational status has not been performed thus far.…”

Section: Introductionmentioning

confidence: 99%

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A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

et al. 2013

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Abstract. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is upregulated in a number of human cancers, including non-small cell lung cancer (NSCLC). Its potential role in NSCLC progression provides an attractive target for anticancer therapy. The expression of phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85α and p110γ subunits of PI3K, phosphorylated p70S6K (p-p70S6K), phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1 (p-4E-BP1) was examined by immunohistochemistry in 102 NSCLC specimens. The results were correlated with clinicopathological features. We also examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2 samples (p.E545K), whereas another sample displayed a rare mutation (p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal metastases.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

et al. 2013

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“…Increased eIF4E expression has been related to progression of malignancy and low patient survival in multiple human cancers, including lymphomas, and cancers in the breast, colon, lung, prostate, and skin. [5][6][7][8][9] Recent studies have also associated the elevated phosphorylation of 4EBP1 with disease progression in ovarian, breast, and prostate cancers. 8,[10][11][12] In addition, the oncogenic potential of eIF4E hyperactivity has been well addressed both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

The synergistic inhibition of breast cancer proliferation by combined treatment with 4EGI-1 and MK2206

et al. 2015

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Abbreviations: eIF4E, eukaryotic translation initiation factor 4E; 4EBP1, eIF4E-binding protein 1; p70S6K, ribosomal p70 S6 kinase; mTORC1, mammalian target of rapamycin complex 1; mTORC2 mammalian target of rapamycin complex 2; PI3K, phosphatidylinositol 3-kinase; ER stress, endoplasmic reticulum stress.Cap-dependent translation is a potential cancer-related target (oncotarget) due to its critical role in cancer initiation and progression. 4EGI-1, an inhibitor of eIF4E/eIF4G interaction, was discovered by screening chemical libraries of small molecules. 4EGI-1 inhibits cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex, and therefore is a potential anti-cancer agent. Here, we report that 4EGI-1 also inhibits mTORC1 signaling independent of its inhibitory role on cap-dependent translation initiation. The inhibition of mTORC1 signaling by 4EGI-1 activates Akt due to both abrogation of the negative feedback loops from mTORC1 to PI3K and activation of mTORC2. We further validated that mTORC2 activity is required for 4EGI-1-mediated Akt activation. The activated Akt counteracted the anticancer effects of 4EGI-1. In support of this model, inhibition of Akt potentiates the antitumor activity of 4EGI-1 both in vitro and in a xenograft mouse model in vivo. Our results suggest that a combination of 4EGI-1and Akt inhibitor is a rational approach for the treatment of cancer.

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“…Elevated level of eIF4E in tumour free surgical margins was correlated with local regional recurrence in patients with HNSCC (Chakraborty et al, 2008). A previous study on lung cancer indicated that the patients with high eIF4E expression showed poor survival after surgery than patients with low eIF4E expression (Wang et al, 2009). The study of breast cancer patients observed that the patients with high expression of eIF4E had significantly higher rate of recurrence and cancer related death (Holm et al, 2008).…”

Section: Introductionmentioning

confidence: 91%

An Australian Retrospective Study to Evaluate the Prognostic Role of p53 and eIF4E Cancer Markers in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC): Study Protocol

Singh¹,

Jayaraj²,

Baxi³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Complete surgical resection of the primary tumour is a crucial predictive step for head and neck squamous cell carcinoma (HNSCC), because incomplete resection may lead to increase in the recurrence rate. Molecular cancer markers have been investigated as potential predictors of prognosis marker, to identify patients who are at high risk of local recurrence. This retrospective study aimed to determine the prognostic correlation between p53 and eIF4E expression and clinical characteristics, recurrence and overall survival. 1-74 months). The Kaplan-Meier method was used to generate recurrence and survival curves. This is a first retrospective study of Northern Territory patients, including Indigenous and non-Indigenous Australians. Molecular study of surgical margins could help to identify patients with and without clear margins after surgery and help in choice of the most appropriate adjuvant treatment for HNSCC patients.

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Overexpression of eukaryotic initiation factor 4E (eIF4E) and its clinical significance in lung adenocarcinoma

Cited by 50 publications

References 25 publications

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

The synergistic inhibition of breast cancer proliferation by combined treatment with 4EGI-1 and MK2206

An Australian Retrospective Study to Evaluate the Prognostic Role of p53 and eIF4E Cancer Markers in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC): Study Protocol

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