title: Cancer cells exploit eIF4E2-directed synthesis of hypoxia response proteins to drive tumor progression.
abstract: Human tumors display considerable diversity in their genetic makeup but share common physiologic attributes such as a hypoxic microenvironment that contribute to the malignant phenotype. Hypoxic cells switch from eukaryotic initiation factor 4E (eIF4E) to eIF4E2 cap-dependent translation to synthesize a portion of their proteins. Here, we show that genetically distinct human cancer cells exploit eIF4E2-directed protein synthesis to form cellular masses larger than approximately 0.15 mm, the diffusion limit of oxygen. Cancer cells depleted of eIF4E2 are indistinguishable from control cells under normoxic conditions, but are unable to survive and proliferate in low oxygen conditions. Activation of eIF4E2-directed translation is essential for cancer cells to form a hypoxic tumor core in in vitro spheroids and to form detectable tumors in in vivo xenograft assays. In contrast, the eIF4E-directed protein synthesis pathway alone cannot sustain cellular adaptation to hypoxia in vitro or confer tumorigenic potential in xenograft assays. These data demonstrate that the phenotypic expression of the cancer genome requires translation by the eIF4E2-directed hypoxic protein synthesis machinery.
authors.affiliation: Authors' Affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Uniacke
authors.forename: J Kishan
authors.initials: JK
authors.lastname: Perera
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lachance
authors.forename: Camille B
authors.initials: CB
authors.lastname: Francisco
authors.forename: Stephen
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D039561:Eukaryotic Initiation Factor-4E; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D014176:Protein Biosynthesis / Q000235:genetics*; D039381:RNA Cap-Binding Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C112609:EIF4E2 protein, human; D039561:Eukaryotic Initiation Factor-4E; D039381:RNA Cap-Binding Proteins