Turning Inhibition of Translation Initiation into Cancer Therapy

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 DESCRIPTION (provided by applicant): The overall goal of this project is to expand our understanding of the cellular and molecular mechanisms that link translation initiation inhibition to apoptosis and tumor suppression triggered by Interleukin-24 (IL-24). Clinical testing of IL-24 as a gene-based therapeutic for the treatment of solid tumors demonstrated that IL-24 is efficacious and is safe. This proposal is consistent with the current view that modern anti-cancer therapy must be target-specific, inhibit the growth of cancer with minimal effect on normal cells, and that effective anti- cancer agents of low toxicity can be achieved by targeting the fundamental mechanisms responsible for the genesis, maintenance, and/or progression of cancer. I have shown that IL-24 causes partial depletion of intracellular Ca++ and activation of endoplasmic reticulum (ER) stress, which in turn induces inhibitory phosphorylation of eukaryotic initiation factor 2 alpha (eIF2). Phosphorylation of eIF2 and the availability of he ternary complex control not only the overall rate of translation, as initially thought, but also th expression of specific gene clusters. The tight translational control of most oncogenic proteins explains the link between unrestricted translation initiation and malignant transformation that has been well established in both experimental models and in numerous human cancers that overexpress translation initiation factors. Phosphorylated eIF2 binds with high affinity to the guanine nucleotide exchange factor eIF2B and thereby inhibits recycling of eIF2*GDP into eIF2*GTP, depleting the ternary complex necessary to initiate a new round of translation. It is well established that partial depletion of ER Ca++ stores activates the eIF2 kinases that phosphorylate eIF2 and thereby limits the rate of translation initiation. Furthermore, I have demonstrated that IL-24 induces expression of Binding immunoglobulin protein (BiP) and C/-EBP homologous protein (CHOP), two down-stream markers of ternary complex abundance. The working hypothesis of this application is that IL-24 exerts anticancer activities because it helps restore physiological restraints on translation initiation. I have demonstrated that Sigma 1 Receptor (Sig1R) interacts with IL-24 and that this IL-24:Sig1R is a critical upstream signal for IL-24-induced ER-stress, calcium mobilization, phosphorylation of eIF2 and apoptosis on cancer cells. In this application we propose to continue our efforts to characterize the cancer cell- specific actions of IL-24 as an inhibitor of translation initiation. Specifically, we will 1)use cameleon calcium indicator proteins to assess directly the calcium content of the ER-stores after IL-24 treatment (Specific Aim 1), 2) determine whether depletion of the ternary complex mediates the anticancer effect of IL-24, (Specific Aim 2), and 3) determine the role of Sig1R on IL-24-mediated inhibition of translation initiation (Specific Aim 3). For these proposed studies we will collaborate with Dr. Jose A. Halperin, from Harvard Medical School, and expert on targeting translation initiation for cancer therapy.