Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer

Arpita De, Blake A Jacobson, Mark S. Peterson, Margaret E. Stelzner, Joe Jay-Dixon, Marian G. Kratzke, Manish R Patel, Peter B Bitterman, Robert A Kratzke

Research output: Contribution to journalArticle

Abstract

Hyperactivation of eIF4F-mediated translation occurs in many if not all cancers. As a consequence, cancer cells aberrantly enhance expression of malignancy-related proteins that are involved in cell cycle progression, angiogenesis, growth, and proliferation. With this in mind eIF4F is a promising molecular target for therapeutics that counteract pathological eIF4F activity. Here we used 4EGI-1, a small-molecule inhibitor of cap-mediated translation that disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex to treat non-small cell lung cancer (NSCLC). Treatment of cells with 4EGI-1 reduced cell proliferation, decreased cap-dependent complex formation, induced apoptosis, enhanced sensitivity to gemcitabine, and altered global cellular translation. Suppression of cap-dependent translation by 4EGI-1 resulted in diminished expression of oncogenic proteins c-Myc, Bcl-2, cyclin D1, and survivin, whereas β-actin expression was left unchanged. In light of these results, small-molecule inhibitors like 4EGI-1 alone or with chemotherapy should be further evaluated in the treatment of NSCLC.

Original languageEnglish (US)
Pages (from-to)157-165
Number of pages9
JournalCancer gene therapy
Volume26
Issue number5-6
DOIs
StatePublished - May 1 2019

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Eukaryotic Initiation Factor-4F
Non-Small Cell Lung Carcinoma
Genome
Growth
gemcitabine
Proto-Oncogene Proteins c-bcl-2
Neoplasms
Cyclin D1
Actins
Cell Cycle
Therapeutics
Cell Proliferation
Apoptosis
Drug Therapy
Proteins

PubMed: MeSH publication types

  • Journal Article

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Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer. / De, Arpita; Jacobson, Blake A; Peterson, Mark S.; Stelzner, Margaret E.; Jay-Dixon, Joe; Kratzke, Marian G.; Patel, Manish R; Bitterman, Peter B; Kratzke, Robert A.

In: Cancer gene therapy, Vol. 26, No. 5-6, 01.05.2019, p. 157-165.

Research output: Contribution to journalArticle

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