Abstract A14: Proteomic analysis of paired malignant and non-malignant tissues from patients with NSCLC adenocarcinoma identified changes in translation initiation factors potentially important in oncogenesis

Abstract

Abstract An important aspect of the control of mRNA translation into protein in mammalian cells is the initiation process, which involves the activities of multiple eukaryotic translation initiation factors or eIFs. Genetic analyses of eIFs in yeast (S. cerevisiae) have defined the eIFs necessary for the basic translation of mRNAs into proteins, but additional subunits found in mammalian cells have not been as well defined in normal cells so how the activities and functions of eIFs may be dysregulated in cancers such as lung cancer are still being determined. Lung cancer causes the highest cancer mortality in men and women in the United States. Lung cancer, mostly non-small cell (NSCLC) adenocarcinoma is responsible for about 13% of all new cancer cases and 26% of all cancer deaths. We undertook a proteomic analysis of lung cancer by analyzing 39 pairs of malignant and non-malignant lung tissues obtained from patients with early stage NSCLC adenocarcinoma using trypsin digestion and tandem MS/MS. Examination of eIFs in these tissues showed significant proteomic differences with significant increases in eIFs, especially in eIF2A, eIF2B, 1 alpha, and eIF2B, 5 episilon (p-values < 0.05). Smaller, but significant increased fold changes were also observed in eIF3B, eIF3G, eIF3J, eIF4G1, eIF4E eIF4A1 and eIF4H. Increased protein levels of EIF2AK2, the interferon induced eIF2A protein kinase was also detected. The eIF2alpha exchange rate may be an important aspect of tumorigenesis in lung cancer tissues with the increased exchange of GTP for GDP in eIF2A, hence the large increases in eIF2B subunits. Increases in eIF3 subunits, especially eIF3j, as well as increases in eIF4E and eIF4G1 correspond to increased protein synthesis rates and cellular proliferation. These early results need further investigation and related functional analysis to determine if the changes in eIFs correspond to important activities in the tumor cells or surrounding microenvironment and have mechanistic consequences in the growth and progression of lung cancer tumors. Citation Format: Suzanne Miyamoto, Johannes F. Fahrmann, Dmitry Grapov, Brett Phinney, Harvey Pass. Proteomic analysis of paired malignant and non-malignant tissues from patients with NSCLC adenocarcinoma identified changes in translation initiation factors potentially important in oncogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A14.