Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells.
Deranged cap-mediated translation is implicated in the genesis, maintenance and progression of many human cancers including mesothelioma. In this study, disrupting the eIF4F complex by antagonizing the eIF4E-mRNA-cap interaction is assessed as a therapy for mesothelioma. Mesothelioma cells were treated with 4Ei-1, a membrane permeable prodrug that when converted to the active drug, 7-benzyl guanosine monophosphate (7Bn-GMP) displaces capped mRNAs from the eIF4F complex. Colony formation was measured in mesothelioma treated with 4Ei-1 alone or combined with pemetrexed. Proliferation was examined in cells treated with 4Ei-1. Binding to a synthetic cap-analogue was used to study the strength of eIF4F complex activation in lysates exposed to 4Ei-1. 4Ei-1 treatment resulted in a dose dependent decrease in colony formation and cell viability. Combination therapy of 4Ei-1 with pemetrexed further reduced colony number. Formation of eIF4F cap-complex decreased in response to 4Ei-1 exposure. 4Ei-1 is a novel prodrug that reduces proliferation, represses colony formation, diminishes association of eIF4F with the mRNA cap, and sensitizes mesothelioma cells to pemetrexed.
Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA.
Esther Z
EZ
Chen
Blake A
BA
Jacobson
Manish R
MR
Patel
Aniekan M
AM
Okon
Shui
S
Li
Kerry
K
Xiong
Abhishek J
AJ
Vaidya
Peter B
PB
Bitterman
Carston R
CR
Wagner
Robert A
RA
Kratzke
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000068437:Pemetrexed; D011355:Prodrugs / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D005971:Glutamates; D015513:Oncogene Proteins; D011355:Prodrugs; D012333:RNA, Messenger; D000068437:Pemetrexed; D006147:Guanine