title: Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F.
abstract: Deregulation of cap-dependent translation is associated with cancer initiation and progression. The rate-limiting step of protein synthesis is the loading of ribosomes onto mRNA templates stimulated by the heterotrimeric complex, eukaryotic initiation factor (eIF)4F. This step represents an attractive target for anticancer drug discovery because it resides at the nexus of the TOR signaling pathway. We have undertaken an ultra-high-throughput screen to identify inhibitors that prevent assembly of the eIF4F complex. One of the identified compounds blocks interaction between two subunits of eIF4F. As a consequence, cap-dependent translation is inhibited. This compound can reverse tumor chemoresistance in a genetically engineered lymphoma mouse model by sensitizing cells to the proapoptotic action of DNA damage. Molecular modeling experiments provide insight into the mechanism of action of this small molecule inhibitor. Our experiments validate targeting the eIF4F complex as a strategy for cancer therapy to modulate chemosensitivity.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6.
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: David R
authors.initials: DR
authors.lastname: Hall
authors.forename: Francis
authors.initials: F
authors.lastname: Robert
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Qui
authors.forename: Iestyn
authors.initials: I
authors.lastname: Lewis
authors.forename: Serdar
authors.initials: S
authors.lastname: Kurtkaya
authors.forename: Ray
authors.initials: R
authors.lastname: Dingledine
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D039562:Eukaryotic Initiation Factor-4F / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors; D057166:High-Throughput Screening Assays; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000502:physiology*
chemical_list: D001565:Benzoates; C113920:EIF4G1 protein, human; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G