Exploit Cellular Weakness Associated with ATE1 Downregulation in Advanced Prostate Cancer
Abstract
Prostate cancer is a major disease affecting men everywhere. Notably, Veterans have higher risk for this disease according to data from the National Academy of Sciences, Engineering, and Medicine. Prostate cancer is very unique because most cases will remain benign, but up to 20% will progress in therapy resistance and metastasis leading to lethality. Our study will directly impact the subpopulation of patients that are highly likely to progress. It will also indirectly affect the rest of the patients by letting them avoid over-treatments. In our previous studies funded by the Idea Development Award for Junior Faculty in 2015, by using cell models, animal models, and human patient samples, we generated multiple lines of evidence pointing out that the progression of prostate cancer is likely contributed by the downregulation of an enzyme called arginyltransferase1 (ATE1). As a brief summary of our achievements, we published six peer-reviewed papers with me as the corresponding author, applied for an international patent (with me as the primary inventor), and trained one graduate student and three postdoctoral researchers (with two of the postdoctoral researchers successfully landing in faculty positions). Based on the substantial amount of data obtained in the last few years, in this proposed study, we will test whether several ATE1-interacting pathways identified in our last study can be exploited as cellular weakness to treat advanced prostate cancer. Therefore, our study will directly address these Overarching Challenges: 1. Develop treatments that improve outcomes for men with lethal prostate cancer. 2. Define the biology of lethal prostate cancer to reduce death. Our study is expected to generate multiple impacts for the translational/clinical studies of prostate cancer treatments. Also, our planned project contains many previously unknown or untested ideas. For example, we will, for the first time, test whether the restriction of the intake of histidine, an amino acid, can be used as an adjuvant therapy to slow down or prevent metastasis and/or the gain of resistance to chemo- or radio-therapies in prostate cancer. The translation of these results to clinical applications should be relatively easy because histidine is not an essential amino acid for adult males, the population affected by prostate cancer. We will also test whether the inhibition of glycolysis can suppress metastasis and/or therapy-resistance in prostate cancer. The feasibilities of these above two ideas are supported by our preliminary data and studies of other groups on several other types of cancers, but were never directly tested in prostate cancer. These results will generate strong interests in the healthcare and research communities related to prostate cancer. Our study will also generate multiple impacts for the basic research fields related to prostate cancer and/or other diseases. ATE1 is the only known enzyme in all animals and human that mediates a posttranslational modification called arginylation. This modification inspires lots of scientific curiosities because it adds an extra arginine to the target protein, therefore changing the de-facto amino acid sequence and the surface charge of the protein. However, the study of ATE1 and arginylation is still a much less explored direction with less than 20 groups in the world (4 in the USA) having working experience. To our knowledge, my group is among the first to investigate the role of ATE1 in prostate cancer. As such, the results of the proposed study will help to fill major gaps of knowledge in the scientific field. Furthermore, the physiological roles of arginylation are still poorly understood. In our study, we will test the consequences of arginylation on two essential proteins, PRPS2 and HIF1alpha in relation to histidine and glucose metabolism. Therefore, our study will significantly advance our understanding about arginylation. Finally, because PRP
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110654
Entities
People
- Fangliang Zhang
Organizations
- United States Army
- University of Miami