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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155069-03
Application #
8433475
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2011-03-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$303,303
Indirect Cost
$108,253
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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
Mao, R-F; Rubio, V; Chen, H et al. (2013) OLA1 protects cells in heat shock by stabilizing HSP70. Cell Death Dis 4:e491
Gupte, Anisha A; Minze, Laurie J; Reyes, Maricela et al. (2013) High-fat feeding-induced hyperinsulinemia increases cardiac glucose uptake and mitochondrial function despite peripheral insulin resistance. Endocrinology 154:2650-62
Sun, Chenglei; Shi, Zheng-Zheng; Zhou, Xiaobo et al. (2013) Prediction of S-glutathionylation sites based on protein sequences. PLoS One 8:e55512