The role of cap-dependent translation in malignant pleural mesothelioma and non-small cell lung cancer.

University of Minnesota Ph.D. dissertation. April 2010. Major: Pharmacology. Advisors: Dr. Robert A.Kratzke, Dr. Peter B. Bitterman. 1 computer file (PDF); xvi, 142 pages. Ill. (some col.)Deregulated cap-dependent translation is a predominant characteristic of malignant cells. Targeting this cap-dependent translation initiation machinery by anti-cancer therapeutics is a very attractive strategy especially because this initiation apparatus functions as a pleotropic integrator and amplifier of numerous oncogenic signals emanating from a wide variety of signaling pathways known to be significantly involved in the pathogenesis of cancer. Preliminary results demonstrate that the ectopic expression of the dominant active translational repressor protein 4E-BP1 effectively suppresses colony formation and tumorigenesis in mesothelioma cells, thus justifying the plausibility of targeting cap-dependent translation in treating this cancer. 4EGI-1 is a novel small molecule inhibitor which has been shown to efficiently disrupt cap-dependent translation by inhibiting the interaction between translation initiation factors eIF4E and eIF4G and enhancing 4E-BP1 association. We report the effect of this small molecule inhibitor, 4EGI-1 on cap-dependent translation in malignant pleural mesothelioma and non-small cell lung cancer. We show that 4EGI-1 effectively inhibits the formation of the cap-dependent translation initiation complex, suppresses cell viability, chemosensitizes the cells, influences expression of certain potential oncogenic proteins and appears to stimulate cell apoptosis by enhancing PARP cleavage. Furthermore, we utilize this novel inhibitor to perform a critical evaluation of the effect of translational control on genome-wide gene expression in these cancers. This was done with the specific objective to unravel known as well as novel target proteins which are differentially expressed in response to alterations in translational efficiency and are thus potentially involved in the progression of these malignancies