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Small-Molecule targeting of translation initiation for cancer therapy.

ABSTRACT: Translation initiation plays a critical role in the regulation of cell growth and tumorigenesis. We report here that inhibiting translation initiation through induction of eIF2? phosphorylation by small-molecular-weight compounds restricts the availability of the eIF2.GTP.Met-tRNAi ternary complex and abrogates the proliferation of cancer cells in vitro and tumor growth in vivo. Restricting the availability of the ternary complex preferentially down-regulates the expression of growth-promoting proteins and up-regulates the expression of ER stress response genes in cancer cells as well as in tumors excised from either animal models of human cancer or cancer patients. These findings provide the first direct evidence for translational control of gene-specific expression by small molecules in vivo and indicate that translation initiation factors are bona fide targets for development of mechanism-specific anti-cancer agents.

SUBMITTER: Aktas BH

PROVIDER: S-EPMC3858549 | biostudies-other | 2013 Oct

REPOSITORIES: biostudies-other

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Small-Molecule targeting of translation initiation for cancer therapy.

Aktas Bertal H BH Qiao Yuan Y Ozdelen Esra E Schubert Roland R Sevinc Sema S Harbinski Fred F Grubissich Luciano L Singer Samuel S Halperin Jose A JA

Oncotarget 20131001 10

Translation initiation plays a critical role in the regulation of cell growth and tumorigenesis. We report here that inhibiting translation initiation through induction of eIF2α phosphorylation by small-molecular-weight compounds restricts the availability of the eIF2.GTP.Met-tRNAi ternary complex and abrogates the proliferation of cancer cells in vitro and tumor growth in vivo. Restricting the availability of the ternary complex preferentially down-regulates the expression of growth-promoting p ...[more]

PMID: 24091475

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