Abstract 4814: Compensatory interplay of p97 segregase and HSP70 chaperone protect cancer cells from heat-induced proteotoxicity

Abstract Due to malignant transformation, cancer cells are characterized by elevated levels of genotoxic, replication or proteotoxic stresses, which makes them vulnerable to various external conditions, including increased temperature. Thus, hyperthermia represents a very effective therapeutic modality usually combined with standard chemotherapy or radiation. Moreover, the elevated temperature is often used in experimental studies related to protein aggregation, cellular heat shock response and other proteostasis mechanisms relevant to cancer progression and treatment. Recently, we developed a single-cell method to inflict defined, subcellular thermal damage, adopting the plasmon resonance principle. Dose-defined heat causes protein damage in subcellular compartments, rapid heat-shock chaperone recruitment, and ensuing engagement of the ubiquitin-proteasome system, providing unprecedented insights into spatiotemporal response to protein damage relevant to cancer. Using this versatile method, we discovered so-far unsuspected compensatory interplay of p97 translocase, the ubiquitin-proteasome system and heat shock protein chaperones in the processing of heat-damaged proteins. As both, p97 and heat shock proteins, represent potential cancer-relevant drug targets, these results can contribute to the development and better implementation of related therapies in cancer treatment. Citation Format: Zdenek Skrott, Katarina Chroma, Petr Muller, Ales Panacek, Jiri Bartek, Martin Mistrik. Compensatory interplay of p97 segregase and HSP70 chaperone protect cancer cells from heat-induced proteotoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4814.