tRNA-Mediated Regulation of Prostate Cancer Biology
Abstract
Prostate cancer is not one disease but instead refers to a variety of types that each derive from distinct causes and therefore merit different treatments. For treatments, it is critical to apply a variety of options that target a wide range of cellular mechanisms. Although existing drugs such as abiraterone/enzalutamide are highly successful in treating prostate cancer, resistance to these drugs inevitably develops over the course of therapy for many patients that can have fatal consequences. It is crucial to develop new classes of molecules that target heretofore unexplored cellular mechanisms, so that tumors not responsive to existing treatment might be responsive to these new routes of therapy. This proposal will explore a new and previously under-appreciated avenue that links prostate cancer drug resistance to an unstudied class of cellular macromolecules in prostate cancer biology. A fundamental step from DNA to protein is translation where the amino acid sequence information encoded by the gene is decoded by transfer RNAs (tRNAs) into proteins. Each human cell type has well-defined levels and patterns of various tRNAs to allow proper regulation of protein synthesis. Historically, it has been difficult to accurately measure tRNA levels and function because of the difficulty of sequencing these high structured and chemically modified RNAs. As a result, tRNA biology and its implications in clinical care have lagged far behind standard DNA and RNA-based studies. We have overcome this barrier by developing a first-in-class technology called MSR-seq that enables the accurate measurements of all tRNAs within a cell. Furthermore, we have adapted this technology to patient specimens. As such, we are poised to conduct the first thorough study of tRNAs in prostate cancer. Our previous studies showed that many cancers have higher levels of tRNA than normal tissues. We also found that a specific tRNA dysregulation can cause cancer. In a new study, we found that drug-resistant prostate cancer cells indeed have different tRNA expression patterns than drug-sensitive cells. In addition, tRNA misregulation can be linked to a decrease in the translation of a tumor suppressor gene that is required to prevent the development of drug-resistance. Our results suggest that tumors use tRNA properties to enable dysregulation of crucial proteins at the translational level. These results challenge the prevailing view that tRNAs are just by-standers in cancer development, progression, and drug resistance. This proposal will capitalize on our new technology and discoveries by identifying the function of tRNA in the regulation of gene expression in human prostate cancer cells and in metastatic prostate cancer tumors. Particular emphasis will be on understanding the basic biology of drug resistant prostate cancer, and on linking tRNA based misregulation to patient outcomes. Our results will identify the potential of using tRNA dependent gene expression in prostate tumors as biomarkers for clinical treatment decisions such as the likelihood of developing drug resistance so that alternative intervention can be considered as early as possible. In addition, we aim to identify new therapeutic targets that may create a new way of targeting drug-resistant prostate cancer. Ultimately, our work will define a new biology of lethal prostate cancer to reduced death among Service Members, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210370
Entities
People
- Tao Pan
Organizations
- United States Army
- University of Chicago