Role of tRNAs in Breast Cancer Tumor Progression
Abstract
Metastasis is a critical step in carcinoma progression and is responsible for more than 90% of cancer-related mortalities and represents a significant financial and logistic burden. Despite intensive research, the cellular and molecular events that specifically control tumor progression and metastasis are poorly understood. While genetic, epigenetic, and transcriptional regulatory mechanisms have received intense investigation and are fairly well documented, in this proposal we wish to investigate the role of tRNAs and the translational machinery as regulators of the radical proteomic reprogramming of cells during tumor progression. Our preliminary data demonstrates preferential ribosomal usage of specific tRNA species during tumor progression and that the increased translational demands of aggressive tumor cells are not met by an increase in tRNA transcription as only a small percentage of the total tRNA pool is actively engaged in translation. Rather, we demonstrate that there is an increased translational utilization of specific tRNAs during cancer progression and that this is coupled to the transcriptional regulation of their cognate aminoacyl-tRNA synthetases (aaRS), essential enzymes that catalyze the production of aminoacyl-tRNAs by loading the amino acids to their cognate, unloaded-tRNAs, thus allowing them to be used by the translational machinery. Thus, the node of tRNA regulation is at the level of aaRSs. At a therapeutic level, the identification of relevant and specific aaRSs demonstrated to be involved in tumor progression is of potential high significance in that specific targeting of relevant aaRS is conceptually more advantageous than an inhibition of tRNA transcription due to the challenge of silencing multiple genes encoding a single tRNA. Importantly, selective aaRS inhibitors are in development or already on the market as antimicrobial and antiparasitic agents and could rapidly be translated into potential anti-cancer therapeutics. Thus, the scientific premise of the proposal is strong, and if successful, will provide not only a molecular and mechanistic delineation of tRNA biology during tumor progression, but also unveil potential novel targets for the development of therapeutics aimed at preventing tumor progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910064
Entities
People
- Philip H Howe
Organizations
- Medical University of South Carolina
- United States Army