Translational control: A target for cancer therapy

doi:10.1016/j.canlet.2007.08.022

Cancer Letters

Volume 258, Issue 1, 8 December 2007, Pages 1-8

https://doi.org/10.1016/j.canlet.2007.08.022 Get rights and content

Abstract

Cap-mediated translation is the default mechanism for the synthesis of proteins in eukaryotic cells. Increasingly, malignant cells have been found to have deregulation of this process. Return of normal translational control is associated with loss of tumorigenic potential in pre-clinical models. Currently, a variety of novel therapeutics are in development targeting this mechanism as a treatment for cancer.

Section snippets

Background

An important level of control of gene expression in eukaryotes occurs at the level of cap-mediated mRNA translation. Regulation of translation is critical for the accurate expression of a broad variety of genes that function in critical processes such as cell cycle progression and differentiation, as well as adaptation to cellular stress [1], [2], [3], [4]. Deregulation at this step is associated with aberrant gene expression leading to altered cell growth and possibly cancer. Translational

Breast cancer

A number of studies have looked at the role of eIF-4E in breast cancer outcome. eIF-4E was observed to be elevated 3- to 30-fold in breast cancer compared with benign breast tissue from non-cancer patients [27], [28], [29]. Increased eIF-4E has been observed in about 50% of ductal carcinoma in situ biopsies [25]. Li et al. analyzed eIF-4E expression in relation to disease parameters and revealed that high eIF-4E over-expression (defined as 7-fold elevation compared with benign breast tissue)

Discussion

eIF-4E plays a critical role in the regulation of cap-dependent protein translation and thus its activity is integral in determining global translation rate. The contribution of eIF-4E to malignant transformation and progression has been extensively elucidated over the past decade. It has been demonstrated in malignant tumors of the breast, head & neck, colon, prostate, bladder, cervix and lung, and has been related to tumorigenesis and disease progression. Ruggero et al. demonstrated that

Conclusions

Translation control has now been recognized as a crucial mechanism to regulate the expression of major regulatory genes involved in cellular functioning, cell cycle progression and differentiation. Further research on translational control and its therapeutic appliance has become increasingly important. However, to date only a limited number of therapeutic drugs are known to affect translational control. Some drugs such as antisense compounds and mTOR inhibitors are being tested in clinical

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Long non-coding RNA EVADR induced by Fusobacterium nucleatum infection promotes colorectal cancer metastasis
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The detection of transcription factors by western blotting and polysome profiling has demonstrated that F. nucleatum can promote translation of Snail, Slug, and Zeb1 mRNAs by upregulating EVADR. Translational regulation is a frequent feature of tumorigenesis and is known to be involved in cancer metastasis (Silvera et al., 2010; Thumma and Kratzke, 2007). lncRNAs play a crucial role in regulating the translational efficiency of mRNAs.
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The Eukaryotic Translation Initiation Factor 4E (eIF4E) as a Therapeutic Target for Cancer
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Translation is mediated partly by regulation of free eukaryotic initiation factor 4E (eIF4E) levels through PI3K-Akt-mTOR signaling. Cancer cells treated with the plant-derived perillyl alcohol (POH) or the mechanistic target of rapamycin (mTOR) inhibitor rapamycin dephosphorylate eIF4E-binding protein (4E-BP1) and attenuate cap-dependent translation. We previously showed in cancer cell lines with elevated eIF4E that POH and rapamycin regulate telomerase activity through this pathway. Here, immortalized Chinese hamster ovary (CHO) control cells and CHO cells with forced eIF4E expression (rb4E) were used to elucidate eIF4E's role in telomerase regulation by POH and rapamycin. Despite 5-fold higher eIF4E amounts in rb4E, telomerase activity, telomerase reverse transcriptase (TERT) mRNA, and TERT protein were nearly equivalent in control and rb4E cells. In control cells, telomerase activity, TERT mRNA and protein levels were unaffected by either compound. In contrast, telomerase activity and TERT protein were both attenuated by either agent in rb4E cells, but without corresponding TERT mRNA decreases indicating a translational/post-translational process. S6K, Akt, and 4E-BP1 were modulated by mTOR mediators only in the presence of increased eIF4E. Thus, eIF4E-overexpression in rb4E cells enables inhibitory effects of POH and rapamycin on telomerase and TERT protein. Importantly, eIF4E-overexpression modifies cellular protein synthetic processes and gene regulation.
Hypoxia-inducible factor-1α (HIF-1α) promotes cap-dependent translation of selective mRNAs through up-regulating initiation factor eIF4E1 in breast cancer cells under hypoxia conditions
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The recruitment of eIF4E1 to eIF4G1 is the key interaction in the eIF4F complex assembly (25, 26). Increased eIF4E1 levels and/or activity have been demonstrated in breast (27, 28), head and neck, colorectal, lung, ovarian (29, 30), prostate (31), bladder (32), brain (33), esophageal (34), and skin and cervical cancers (28, 35) as well as lymphomas (8, 36). The human eIF4E family consists of three members: eIF4E1, eIF4E2 (4EHP; 4E-LP), and eIF4E3 (37, 38).
Hypoxia promotes tumor evolution and metastasis, and hypoxia-inducible factor-1α (HIF-1α) is a key regulator of hypoxia-related cellular processes in cancer. The eIF4E translation initiation factors, eIF4E1, eIF4E2, and eIF4E3, are essential for translation initiation. However, whether and how HIF-1α affects cap-dependent translation through eIF4Es in hypoxic cancer cells has been unknown. Here, we report that HIF-1α promoted cap-dependent translation of selective mRNAs through up-regulation of eIF4E1 in hypoxic breast cancer cells. Hypoxia-promoted breast cancer tumorsphere growth was HIF-1α-dependent. We found that eIF4E1, not eIF4E2 or eIF4E3, is the dominant eIF4E family member in breast cancer cells under both normoxia and hypoxia conditions. eIF4E3 expression was largely sequestered in breast cancer cells at normoxia and hypoxia. Hypoxia up-regulated the expression of eIF4E1 and eIF4E2, but only eIF4E1 expression was HIF-1α-dependent. In hypoxic cancer cells, HIF-1α-up-regulated eIF4E1 enhanced cap-dependent translation of a subset of mRNAs encoding proteins important for breast cancer cell mammosphere growth. In searching for correlations, we discovered that human eIF4E1 promoter harbors multiple potential hypoxia response elements. Furthermore, using chromatin immunoprecipitation (ChIP) and luciferase and point mutation assays, we found that HIF-1α utilized hypoxia response elements in the human eIF4E1 proximal promoter region to activate eIF4E1 expression. Our study suggests that HIF-1α promotes cap-dependent translation of selective mRNAs through up-regulating eIF4E1, which contributes to tumorsphere growth of breast cancer cells at hypoxia. The data shown provide new insights into protein synthesis mechanisms in cancer cells at low oxygen levels.
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Conclusion: HIF-1α promotes cap-dependent translation of selective mRNAs through up-regulating eIF4E1 in cancer cells at hypoxia.
Significance: Our study provides new insights into the translation mechanisms in cancer cells under low O₂ concentrations.

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Mini-reviewTranslational control: A target for cancer therapy

Abstract

Section snippets

Background

Breast cancer

Discussion

Conclusions

Cell

Cell

Prog. Nucl. Acid Res. Mol. Biol.

J. Biol. Chem.

Mod. Pathol.

Am. J. Pathol.

Hum. Pathol.

J. Urol.

J. Biol. Chem.

Curr. Opin. Pharmacol.

Cancer Cell

Kidney Int.

Cell

Translational control of protein synthesis

Annu. Rev. Biochem.

Pathway and mechanism of initiation of protein synthesis

Essentials of signal transduction

eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation

Annu. Rev. Biochem.

eIF4E-from translation to transformation

Oncogene

Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis

Anticancer Res.

Regulation of translation initiation by FRAP/mTOR

Genes Dev.

eIF-4E expression and its role in malignancies and metastases

Oncogene

mRNAs containing extensive secondary structure in their 5′ noncoding region translate efficiently in cells over expressing initiation factor eIF-4E

EMBO J.

Translational regulation of vascular permeability factor by eukaryotic initiation factor 4E: implications for tumor angiogenesis

Int. J. Cancer

Translational enhancement of FGF-2 by eIF-4 factors, and alternate utilization of CUG and AUG codons for translation initiation

Oncogene

The role of c-myc in regulation of translation initiation

Oncogene

Elevated levels of cyclin D1 in response to increased expression of eukaryotic initiation factor 4E

Mol. Cell Biol.

Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E

Proc. Natl. Acad. Sci. USA

The emerging role for the mRNA cap-binding protein, eIF-4E, in metastatic progression

Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs

Clin. Exp. Metastasis

Regulation of 4EBP1 phosphorylation: a novel two-step mechanism

Genes Dev.

Hierarchical phosphorylation of the translation inhibitor 4E-BP1

Genes Dev.

4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt (PKB) signaling pathway

Genes Dev.

Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR

Proc. Natl. Acad. Sci. USA

Elevated expression of eIF-4E in confined early breast cancer lesions: possible role of hypoxia

Int. J. Cancer

Over expression of hypoxia-inducible factor 1alpha in common human cancers and their metastases

Cancer Res.

Int. J. Cancer

Overexpression of eukaryotic initiation factor 4E (eIF4E) in breast carcinoma

Cancer

Differential expression of vascular endothelial growth factor mRNA vs. protein isoform expression in human breast cancer and relationship to elF-4E

Br. J. Cancer

Mini-review
Translational control: A target for cancer therapy