An Unknown Role of Arginylation in Prostate Cancer
Abstract
The progression of prostate cancer to metastasis is difficult to predict and manage. Current clinical practice solely relies on Gleason scoring, which is based on tissue morphology and therefore difficult to be standardized. Furthermore, up to 50% of patients in clinical practice are categorized as Gleason grade 7, which is an intermediate rank, lacking reliable predictive precision. Identifying a biomarker to facilitate the prediction of prostate cancer metastasis is highly desirable. Currently, there is no such biomarker, mainly due to the lack of understanding of the molecular mechanism of prostate cancer progression. In our recent data-mining of a prostate cancer sample database from non-hypothesis-driven studies, we identified a downregulation of arginyltransferase (Ate1) in metastatic/invasive stages of prostate cancer, and an association of the lower transcription level of Ate1 in the primary tumor with the eventual metastatic outcome, suggesting that the level of Ate1 may be able to serve as a predictive marker for metastasis of prostate cancer. Ate1 is solely responsible for arginylation, a post-translational modification that adds one extra arginine to the target protein. Arginylation has been shown to promote ubiquitination, a common signal for degradation of the target protein. In addition to the degradative effect, arginylation may also modify the function of the target protein and is known to affect the dynamics of the cytoskeleton, the scaffold of cells. Previous research also suggested that the arginylation reaction is regulated by oxidative stress, which is a known risk factor for prostate cancer. In our preliminary study, we discovered that Ate1 is upregulated by oxidative stress and that the increase of Ate1 is essential for programmed cell death (apoptosis) during cellular response to oxidative stress. We further found that a depletion of Ate1 leads to cancer-like behaviors in cells, including the growth of tumor-like masses in immune compromised mice and the loss of contact inhibition, which is a key event separating cancerous cells from normal cells. This evidence leads us to suspect that Ate1 and its arginylation activity is an essential factor for initiating programmed cell death during stress response. The suppression of this pathway, as observed in the prostate cancer samples from human patients, is therefore likely responsible for promoting the progression of cancer. On this foundation, we further propose that the level of Ate1 protein in the primary tumor of prostate has the potential to be used as a novel maker for predicting metastasis of prostate cancer. To prove our hypothesis, we will first use cells and animals to test the molecular mechanism we proposed. We will then use patient samples retrieved from our tissue bank to directly test whether a lower level of Ate1 protein in the primary tumor is indeed associated with a metastatic outcome or other clinical criteria in human. Finally, we will use newly developed techniques including a modified mass spectrometry application to generate a comprehensive list of the degradation targets of arginylation in response to oxidative stress. We will also test whether the arginylation modification of a protein fragment is involved in the anti-cancer role of Ate1. Our research, if successful, will lead to the identification of the first effective biomarker to predict the metastasis of prostate cancer. The data generated from this grant will also lead to many opportunities for series of mechanistic studies for further understanding of the progression of prostate cancer, as well as for finding novel drug targets for this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510715
Entities
People
- Fangliang Zhang
Organizations
- United States Army
- University of Miami