Abstract 5788: Targeting p97-NPL4 pathway by copper chelators

Abstract

Abstract Copper chelators forming stable complexes, such as the bis(diethyldithiocarbamate)-copper complex (CuET), derived from Antabuse (disulfiram, DSF), have shown pronounced anticancer activity. CuET induces aggregation of NPL4, a crucial cofactor of the p97 segregase in the ubiquitin-proteasome system, leading to proteotoxic stress and subsequent cancer cell death. Our study investigates whether NPL4 inhibition is unique to CuET or extends to other dithiocarbamate-copper complexes and distinct copper chelators. Utilizing a cellular NPL4 aggregation screening assay, we examined various chelators for their ability to induce NPL4 aggregation. Our findings reveal that this capacity is relatively common among structurally diverse DTCs-copper complexes and other unrelated copper chelators. Compounds that caused NPL4 aggregation also triggered NPL4-p97 complex immobilization, polyubiquitinated protein accumulation, and unfolded protein and heat shock responses. These responses correlated strongly with cancer cell cytotoxicity, particularly potent at nanomolar concentrations, underscoring NPL4 as a critical target. Our results demonstrate the broad potential of copper chelators in targeting NPL4, inducing lethal proteotoxic stress in cancer cells, and offering significant implications for drug development. Citation Format: Martin Mistrik, Zdenek Skrott, Martin Loffelmann. Targeting p97-NPL4 pathway by copper chelators [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 5788.