title: STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A.
abstract: The transcription factor STAT1 displays antitumor functions for certain forms of cancer via immunoregulatory and cell-autonomous pathways. Paradoxically, STAT1 can promote the survival of different tumor types treated with chemotherapeutic drugs through mechanisms that are not clearly defined. Herein, we demonstrate that STAT1 displays prosurvival effects in human KRAS colon tumor cells by regulating pathways that converge on the initiation of mRNA translation. Specifically, STAT1 increases PI3K class IB signaling and promotes the downregulation of the programmed cell death protein 4 (PDCD4), a protein with tumor-suppressive properties. PDCD4 downregulation by STAT1 increases the activity of the translation initiation factor eIF4A, which facilitates the cap-independent translation of mRNAs encoding for the antiapoptotic XIAP and BCL-XL in colon tumors with mutated but not normal KRAS Genetic inactivation of STAT1 impairs the tumorigenic potency of human KRAS colon tumor cells and renders them resistant to the antitumor effects of the pharmacologic inhibition of eIF4A in culture and immunodeficient mice. Our data demonstrate an important connection between mRNA translation and KRAS tumorigenesis under the control of STAT1, which can determine the susceptibility of KRAS tumors to pharmacologic inhibition of mRNA translation initiation. Mol Cancer Ther; 15(12); 3055-63. ©2016 AACR.
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Cedric
authors.initials: C
authors.lastname: Darini
authors.affiliation: Laboratoire d'Innovation Thérapeutique (UMR 7200), Faculté de Pharmacie de l'Université de Strasbourg, Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désaubry
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. antonis.koromilas@mcgill.ca.|Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D047368:Tumor Burden; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; C117307:KRAS protein, human; D050794:STAT1 Transcription Factor; D014157:Transcription Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D019869:Phosphatidylinositol 3-Kinases; D016283:Proto-Oncogene Proteins p21(ras)