title: Small molecule inhibitors of IRES-mediated translation.
abstract: Many genes controlling cell proliferation and survival (those most important to cancer biology) are now known to be regulated specifically at the translational (RNA to protein) level. The internal ribosome entry site (IRES) provides a mechanism by which the translational efficiency of an individual or group of mRNAs can be regulated independently of the global controls on general protein synthesis. IRES-mediated translation has been implicated as a significant contributor to the malignant phenotype and chemoresistance, however there has been no effective means by which to interfere with this specialized mode of protein synthesis. A cell-based empirical high-throughput screen was performed in attempt to identify compounds capable of selectively inhibiting translation mediated through the IGF1R IRES. Results obtained using the bicistronic reporter system demonstrate selective inhibition of second cistron translation (IRES-dependent). The lead compound and its structural analogs completely block de novo IGF1R protein synthesis in genetically-unmodified cells, confirming activity against the endogenous IRES. Spectrum of activity extends beyond IGF1R to include the c-myc IRES. The small molecule IRES inhibitor differentially modulates synthesis of the oncogenic (p64) and growth-inhibitory (p67) isoforms of Myc, suggesting that the IRES controls not only translational efficiency, but also choice of initiation codon. Sustained IRES inhibition has profound, detrimental effects on human tumor cells, inducing massive (>99%) cell death and complete loss of clonogenic survival in models of triple-negative breast cancer. The results begin to reveal new insights into the inherent complexity of gene-specific translational regulation, and the importance of IRES-mediated translation to tumor cell biology.
authors.affiliation: a Comprehensive Cancer Center; University of Alabama at Birmingham ; Birmingham , AL USA.|b Department of Medicine , Division of Hematology / Oncology; University of Alabama at Birmingham ; Birmingham , AL USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Vaklavas
authors.affiliation: c Department of Biochemistry and Molecular Genetics; University of Alabama at Birmingham ; Birmingham , AL USA.|d Current address: Analytical Development Department; Novavax Inc. ; Gaithersburg , MD USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: a Comprehensive Cancer Center; University of Alabama at Birmingham ; Birmingham , AL USA.|b Department of Medicine , Division of Hematology / Oncology; University of Alabama at Birmingham ; Birmingham , AL USA.|e Current address: Department of Pediatrics; Seoul National University Bundang Hospital; Gyeonggi-do , Korea.
authors.forename: Hyoungsoo
authors.initials: H
authors.lastname: Choi
authors.affiliation: a Comprehensive Cancer Center; University of Alabama at Birmingham ; Birmingham , AL USA.|f Department of Pathology; University of Alabama at Birmingham ; Birmingham , AL USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: a Comprehensive Cancer Center; University of Alabama at Birmingham ; Birmingham , AL USA.|b Department of Medicine , Division of Hematology / Oncology; University of Alabama at Birmingham ; Birmingham , AL USA.|f Department of Pathology; University of Alabama at Birmingham ; Birmingham , AL USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
authors.affiliation: a Comprehensive Cancer Center; University of Alabama at Birmingham ; Birmingham , AL USA.|b Department of Medicine , Division of Hematology / Oncology; University of Alabama at Birmingham ; Birmingham , AL USA.|c Department of Biochemistry and Molecular Genetics; University of Alabama at Birmingham ; Birmingham , AL USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Blume
mesh_terms: D049109:Cell Proliferation; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014162:Transfection
chemical_list: D000067556:Internal Ribosome Entry Sites; D016271:Proto-Oncogene Proteins c-myc
keywords: IGF1R; Internal ribosome entry site (IRES); c-Myc; gene-specific translational regulation; triple-negative breast cancer