Abstract 3174: Crosstalk between protein translation and DNA replication during stress response and cancer therapy

Abstract

Abstract Tumor microenvironment, which includes both various types of cells (tumor cells, stromal cells, immune cells, etc.) and an interstitial fluid system, plays a key role in tumorigenesis, therapy response, and disease outcome. While the cell component has been heavily studied in cancer treatment, the interstitial fluid system has not. A key feature of the fluid system is constant oscillation of osmolytes such as salt, glucose, and proteins due to unstable blood supply and tumor metabolism, resulting in cycles of osmotic stress and recovery. Yet, how this osmotic stress - recovery cycle mediates tumorigenesis and cancer therapy remains poorly understood. Our unpublished results reveal sequential activation of molecular events during osmotic stress and recovery. In the stress stage, protein translation, transcription, and DNA replication are inhibited. Following recovery, protein translation resumes, gene transcription is greatly upregulated, but DNA replication is not immediately recovered. It turns out that a DNA replication checkpoint is activated during recovery; as a result, DNA replication is halted. Defects in activating protein translation inhibition during stress fail to activate the replication checkpoint during recovery, indicating a causative link from protein translation inhibition to DNA replication checkpoint activation. Many genes involved in this crosstalk are altered in a wide range of human tumors. Ovarian cancer cells that are resistant to standard of care (for instance, cisplatin) demonstrate defects in this crosstalk; however, they were also more sensitive to a combination of osmotic stress followed by the presence of replication checkpoint inhibitors during recovery than parental cancer cells. These findings highlight a unique role of the interstitial fluid system in tumor development and therapy response. They also suggest a new anticancer strategy by combining osmotic stress with checkpoint inhibitors. Key words: Tumor microenvironment; osmotic stress; protein translation control; DNA replication checkpoint; cancer therapy Citation Format: Fangfang Wang. Crosstalk between protein translation and DNA replication during stress response and cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3174.