Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells

Abstract

Elevated levels of eukaryotic translation initiation factor 4E (eIF4E) enhance translation of many malignancy-related proteins, such as vascular endothelial growth factor (VEGF), c-Myc and osteopontin. In non-small-cell lung cancer (NSCLC), levels of eIF4E are significantly increased compared with normal lung tissue. Here, we used an antisense oligonucleotide (ASO) to inhibit the expression of eIF4E in NSCLC cell lines. eIF4E levels were significantly reduced in a dose-dependent manner in NSCLC cells treated with eIF4E-specific ASO (4EASO) compared with control ASO. Treatment of NSCLC cells with the 4EASO resulted in decreased cap-dependent complex formation, decreased cell proliferation and increased sensitivity to gemcitabine. At the molecular level, repression of eIF4E with ASO resulted in decreased expression of the oncogenic proteins VEGF, c-Myc and osteopontin, whereas expression of β-actin was unaffected. Based on these findings, we conclude that eIF4E-silencing therapy alone or in conjunction with chemotherapy represents a promising approach deserving of further investigation in future NSCLC clinical trials.

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…eIF4E stimulates the nuclear transport of mRNAs housing an eIF4E-sensitivity element. Notably, these mRNAs encode proteins associated with growth and malignancy [18]. For example, eIF4E regulates the expression of E3 ubiquitin-protein ligase, an important negative regulator of p53.…”

Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies

“…The c-Myc protein has a short half-life of ,30 minutes, 4 and the complex secondary structures in the 59 untranslated region (UTR) of MYC messenger RNA (mRNA) make its translation highly dependent on the eukaryotic translation initiation factor 4F (eIF4F). 5,6 eIF4F exists as a complex composed of the eIF4E, eIF4A, and eIF4G subunits. eIF4E can be sequestered by eIF4E-binding protein 1 (4E-BP1), which acts as a "brake" for initiation of mRNA translation.…”

eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma

“…As these weak mRNAs almost universally encode growth regulatory proteins, including C-myc, Cyclin D1, Bcl-2, Survivin, FGF-2, VEGF, and MMP-9 etc [5, 10]. They were reported to promote the tumor cells resistance to apoptosis, proliferation, invasion and distant metastasis, even drug resistance induced by increased eIF4E [10, 14–17]. The present study have clarified the oncogenic role of eIF4E in ESCC, and confirmed that the weak mRNAs including C-myc, Cyclin D1, Bcl-2, Survivin, FGF-2, VEGF, and MMP-9 were regulated by eIF4E in ESCC cell line.…”

“…Proliferation of malignant tissue needs variable proteins continual synthesis, thus over-expression of eIF4E is an inevitable event. Recent studies have revealed that excessive eIF4E could change cell phenotype and participate in the induction of cell proliferation, cell transformation and tumorigenesis, invasion and metastasis [10, 14–17]. Excessive expression of eIF4E is significantly correlated with unfavorable clinical outcomes such as pathological grading of tumor, high cellular proliferation, and poor prognosis in several cancers.…”

“…Excessive expression of eIF4E is significantly correlated with unfavorable clinical outcomes such as pathological grading of tumor, high cellular proliferation, and poor prognosis in several cancers. Importantly, eIF4E has been regarded as a novel target to synergize drug efficiency through multiple pathways intervention [10, 14, 18, 19]. …”