Small-molecule targeting of translation initiation for cancer therapy
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Bertal H. Aktas1,2, Yuan Qiao2, Esra Ozdelen2, Roland Schubert2, Sema Sevinc2, Fred Harbinski2, Luciano Grubissich2, Samuel Singer3, Jose A. Halperin1,2
1 Department of Medicine, Brigham and Women’s Hospital, Boston;
2 Laboratory for Translational Research, Harvard Medical School, Boston;
3 Department of Surgery, Brigham and Women’s Hospital, Boston.
Jose A. Halperin, email:
Keywords: CANCER, TERNARY COMPLEX, TRANSLATION, eIF2, UTR
Received: July 15, 2013 Accepted: August 12, 2013 Published: August 14, 2013
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 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.
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