Abstract 3770: tRNA-mediated regulation of nutrient-responsive pathways in breast cancer cell

Abstract

Abstract Autophagy or macroautophagy plays a crucial role in the survival of metabolic-stressed tumor cells by providing sufficient intracellular nutrients and energy to sustain growth. Cancer cells experiencing nutritional stress take advantage of the autophagic pathway to maintain viability. When cells experience nutritional stress, the activity of the serine/threonine kinase mTOR is downregulated, leading to reduced protein synthesis and subsequently increased autophagy. Under these conditions tRNAs, which are essential components of the protein synthesis machinery, accumulate in the nucleus. Cancer cells are often nutrient-starved, yet they still grow and proliferate, which indicates that sufficient amino acid-charged tRNAs are present in the cytosol to support protein synthesis. Our studies in human fibroblasts have shown that accumulation of tRNA in the nucleus, caused by reduced expression of the tRNA-transporting karyopherin Xpo-t, induces a starvation-like response, i.e. activity of the mTOR1C1 pathway is reduced and autophagy upregulated. Thus, we hypothesize that nuclear accumulation of tRNA signals cellular starvation. In this work, we aim to determine if tRNA accumulation in the nucleus, accomplished by reduced expression of tRNA transporting karyopherin Xpo-t, induces a starvation response in breast cancer cells. Using MDA-MB-231 breast cancer cells as a model system for our in-vitro studies, we have shown significant response to nutrient starvation with regard to autophagy. We are currently analyzing if shRNA-mediated knockdown of Xpo-t in MDA-MB-231 cells triggers a starvation-response. Subsequently, we will determine if starvation in combination with Xpo-t knockdown lead to upregulation of autophagy and reduction of mTOR to such level that induces cancer cell death. Additional studies will be done to examine such response in other breast cancer cells and will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2011-3770