The eukaryotic translation initiation factor 4E (eIF4E) is frequently overexpressed in human cancers and contributes to cancer development and progression by selectively driving translation of genes that are essential for cancer cell growth and survival (e.g., c-myc, VEGF, BCL-2). In the past decades accumulating evidence has demonstrated that down-regulation of eIF4E expression in cancer cells can be an effective strategy for therapeutic intervention of cancer. Indeed, eIF4E antisense oligonucleotides have been shown to inhibit tumor growth without toxicity to host animals, and have entered clinical trials. However, because of the lack of a reliable assay that can be used in high-throughput drug screening, no small molecule that can inhibit eIF4E expression in cancer cells is currently available for clinical testing. This application is in response to the NIH Program Announcement PA-10-213, """"""""Development of Assays for High-Throughput Screening for Use in Probe and Pre-therapeutic Discovery"""""""", and will address the imperative need of a high-throughput screening (HTS) assay for discovery of drug leads that target eIF4E expression in cancer cells. Specifically, our objective is to utilize emerging cell-engineering technologies to develop an innovative assay in which a bioluminescent reporter integrated in the native eIF4E gene locus is expressed under control of the endogenous eIF4E promoter. Such an assay is expected to overcome limitations of current reporter assays that are mostly based on cloned, transgenic promoters, which often lack essential distal/intronic cis-regulatory elements while residing in foreign chromatin environments. Therefore, the innovative assay would faithfully reproduce responses of the endogenous eIF4E gene to chemical treatments and thus be more reliable in high-throughput search for small molecules inhibitory for eIF4E expression. Accordingly, the specific aims of this project are: (1) to develop cell lines harboring a reporter gene in the native eIF4E gene locus for high-throughput drug screening, (2) to develop secondary assays for identification of false positives and prioritization of screening hits for further drug development. Completion of the proposed research will result in an innovative HTS assay useful for developing therapeutic agents that can cure cancer through inhibiting eIF4E expression. Therefore, the proposed studies will impact health of millions of people afflicted with cancer. This application will also provide a proof of concept for an innovative drug-discovery strategy that can be applied to search for agents targeting any given gene aberrantly expressed in cancer thereby significantly advancing targeted cancer therapy.
The objective of this project is to develop an innovative screening assay for use in discovery of therapeutic agents targeting eIF4E - a protein commonly overexpressed in human cancers. Ultimately, completion of the proposed research will lead to the development of novel cancer therapies, and thereby benefit millions of people afflicted with cancer.
|Cui, Hongmei; Li, Xingyao; Han, Chunhua et al. (2016) The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins. J Biol Chem 291:10847-57|
|Wang, Ziyan; Yan, Chunhong (2016) Emerging roles of ATF3 in the suppression of prostate cancer. Mol Cell Oncol 3:e1010948|
|Zhao, Jonathan; Li, Xingyao; Guo, Mingxiong et al. (2016) The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and H3K27ac for transcriptional regulation. BMC Genomics 17:335|
|Wang, Z; Kim, J; Teng, Y et al. (2016) Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5(+)CK8(+) epithelial cells. Oncogene 35:3555-64|
|Wang, Z; Xu, D; Ding, H-F et al. (2015) Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene 34:4975-84|
|Lang, Liwei; Ding, Han-Fei; Chen, Xiaoguang et al. (2015) Internal Ribosome Entry Site-Based Bicistronic In Situ Reporter Assays for Discovery of Transcription-Targeted Lead Compounds. Chem Biol 22:957-64|
|Cui, Hongmei; Guo, Mingxiong; Xu, Dong et al. (2015) The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nat Commun 6:6752|
|Lang, Liwei; Liu, Xiaoyu; Li, Yan et al. (2014) A synthetic manassantin a derivative inhibits hypoxia-inducible factor 1 and tumor growth. PLoS One 9:e99584|
|Wei, Saisai; Wang, Hongbo; Lu, Chunwan et al. (2014) The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins. J Biol Chem 289:8947-59|
|Lu, Chunwan; Liu, Di; Jin, Jing et al. (2013) Inhibition of gastric tumor growth by a novel Hsp90 inhibitor. Biochem Pharmacol 85:1246-56|
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