Most cancer-related deaths are caused by metastases rather than the primary tumor. Anti-metastasis therapy holds promise to convert the fatal disease to a manageable chronic disease. The overall goal of this project is to establish a novel anti-metastasis mechanism by targeting OLA1, a newly discovered posttranslational regulator of cellular stress response. Recent studies have shown that knockdown of OLA1 in cancer cells results in reduced migration and invasion but enhanced detachment-induced cell death (anoikis), suggesting a possible indication of OLA1-inhibition in anti-metastasis therapy. In this project OLA1 will be validated as a therapeutic target for cancer metastasis by using animal models of human breast cancer (""""""""target validation""""""""). Meanwhile Ola1-knockout mice will be analyzed to predict systemic side-effects that might result from the use of future OLA1 inhibitor (""""""""safety evaluation""""""""). It is hypothesized in this project that OLA1 is an upstream negative regulator of protein S-glutathionylation (the reversible binding of glutathione to protein thiols), and inhibition of OLA1 can result in increased glutathionylation in many cellular proteins including actin leading to impaired cell migration and invasion. This hypothesis will be tested by studying the knockout mice, mouse embryonic fibroblast cells, and cancer cells using a panel of conventional and proteomics technologies (""""""""biological hypothesis""""""""). Finally, the druggability of OLA1 will be explored by performing initial high-throughput screening (HTS) based on the ATPase or ATP-binding activities of OLA1. The results of this test will provide assessment of whether the development of small molecular inhibitor of OLA1 is feasible (""""""""druggability test""""""""). Overall this project consists of all critical components of target validation processes, and if successful, these will lead to a whole new strategy for the treatment of metastasis, as well as major advances in understanding the function of OLA1 and the regulation of protein glutathionylation pathway.
This project is to establish a novel strategy to treat metastatic cancer based on targeting OLA1, a newly discovered cellular stress response protein and also an endogenous regulator of the posttranslational glutathionylation pathway.
|Bai, Li; Yu, Zubin; Zhang, Jiawei et al. (2016) OLA1 contributes to epithelial-mesenchymal transition in lung cancer by modulating the GSK3?/snail/E-cadherin signaling. Oncotarget 7:10402-13|
|Ding, Zonghui; Liu, Yue; Rubio, Valentina et al. (2016) OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression. Mol Cell Biol 36:2568-82|
|Xu, Dong; Song, Renduo; Wang, Guohui et al. (2016) Obg-like ATPase 1 regulates global protein serine/threonine phosphorylation in cancer cells by suppressing the GSK3?-inhibitor 2-PP1 positive feedback loop. Oncotarget 7:3427-39|
|Chen, Huarong; Song, Renduo; Wang, Guohui et al. (2015) OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation. Sci Rep 5:13241|
|Khan, I M; Perrard, X Yd; Brunner, G et al. (2015) Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance. Int J Obes (Lond) 39:1607-18|
|Guo, Chuan Fei; Liu, Qihan; Wang, Guohui et al. (2015) Fatigue-free, superstretchable, transparent, and biocompatible metal electrodes. Proc Natl Acad Sci U S A 112:12332-7|
|Jeyabal, Prince V S; Rubio, Valentina; Chen, Huarong et al. (2014) Regulation of cell-matrix adhesion by OLA1, the Obg-like ATPase 1. Biochem Biophys Res Commun 444:568-74|
|Andersson, Helen A; Kim, Yoo-Shin; O'Neill, Brian E et al. (2014) HSP70 promoter-driven activation of gene expression for immunotherapy using gold nanorods and near infrared light. Vaccines (Basel) 2:216-27|
|Zeng, Zihua; Parekh, Parag; Li, Zheng et al. (2014) Specific and sensitive tumor imaging using biostable oligonucleotide aptamer probes. Theranostics 4:945-52|
|Ghosh, Pradip; Zhang, Jiawei; Shi, Zheng-Zheng et al. (2013) Synthesis and evaluation of an imidazole derivative-fluorescein conjugate. Bioorg Med Chem 21:2418-2425|
Showing the most recent 10 out of 16 publications