TY - JOUR
T1 - Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer
AU - De, Arpita
AU - Jacobson, Blake A.
AU - Peterson, Mark S.
AU - Stelzner, Margaret E.
AU - Jay-Dixon, Joe
AU - Kratzke, Marian G.
AU - Patel, Manish R.
AU - Bitterman, Peter B.
AU - Kratzke, Robert A.
N1 - Publisher Copyright:
© 2018, Springer Nature America, Inc.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056630947&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056630947&partnerID=8YFLogxK
U2 - 10.1038/s41417-018-0058-6
DO - 10.1038/s41417-018-0058-6
M3 - Article
C2 - 30420719
AN - SCOPUS:85056630947
SN - 0929-1903
VL - 26
SP - 157
EP - 165
JO - Cancer gene therapy
JF - Cancer gene therapy
IS - 5-6
ER -