Adaptation to stress is an integral part of cancer progression and resistance to therapies. Stress stimuli induce the formation of discrete cytoplasmic foci known as stress granules (SGs), which recruit critical regulators of cellular homeostasis and stalled mRNA complexes. Emerging evidence indicates that SG formation is a critical component of the integrated stress response. SGs are dynamic structures;their formation is regulated by RNA binding proteins, several of which are known oncogene effectors. Accordingly, SGs may be targets of oncogene regulation.
The aim of this project is to investigate the role of oncogenic Ras in SG formation and the subsequent effects on cell survival under stress. To accomplish this we will: 1) investigate how SG dynamics are altered in response to oncogenic Ras;2) define the molecular framework for Ras-regulated SG formation;3) examine how Ras-regulated SG formation contributes to the enhanced stress resistance of cancer cells and tumorigenesis. Altogether, these studies should provide new and significant insight into the role of oncogenic Ras in stress response mechanisms as well as new targets for therapeutic interventions.
The relevance of the research proposed in this application is emphasized by the fact that cancer tissues are known to be more resistant to stress stimuli than their normal counterparts. This characteristic can interfere with the efficacy of radiotherapy and chemotherapy, which relies on stress-induced cell death to be effective. Consequently, the understanding of the mechanisms that govern the stress resistance of cancer cells is instrumental to the comprehension and the development of better treatments for this lethal disease.