Abstract 2665: Zinc dysregulation as an emerging molecular target in epithelial cancers

Abstract

Abstract Zinc plays an established role in structure and function of enzymes and transcription factors, and zinc signaling has now been recognized as a molecular determinant of epithelial differentiation and cell fate. Intracellular zinc homeostasis is regulated by zinc importers (ZIPs encoded by the SLC39A gene family). Cumulative evidence suggests that dysruption of zinc homeostasis is an emerging hallmark of various tumor types, characterized by downregulation of ZIP expression upstream of intracellular zinc depletion. In nonmelanoma skin cancer (NMSC) examined in TMA format we have observed downregulation of ZIP2 (involved in epidermal differentiation) that occurs with zinc depletion and impaired differentiation. Likewise, in pancreatic ductal adenocarcinoma (PDAC) tumor tissue, downregulation of ZIP3 and zinc depletion are detectable. We therefore tested feasibility of pharmacological induction of intracellular zinc overload for chemotherapeutic intervention. Using the small molecule ionophore ZnPT (zinc pyrithione) as an experimental chemotherapeutic, rapid induction of zinc overload followed by metal stress response signaling and cell death were observable in a panel of malignant epithelial cell lines (NMSC: SCC-25; HaCaT-ras II-4; PDAC: BxPC-3, MIA PaCa-2, PANC-1). Remarkably, PDAC cell lines displayed nanomolar sensitivity to ZnPT-induced cytotoxicity. In BxPC-3 cells, pronounced upregulation of stress response gene expression (MT2A, HSPA6, HMOX1) and signaling (p-p38, p-eIF2α, HO-1) was detectable within one hour of ZnPT exposure. Accumulation of protein-ubiquitin conjugates further substantiated the rapid occurrence of ZnPT-induced proteotoxic stress and UPR, consistent with a role of ZnPT in the inhibition of proteasome-associated deubiquitinating enzymes (DUBs). Next, we confirmed NMSC-directed anti-tumor activity of ZnPT in a photocarcinogenesis SKH1 mouse model, followed by exploratory chemotherapeutic intervention targeting BxPC-3 PDAC xenografts. Taken together, our data suggest that ZIP-based dysruption of intracellular zinc homeostasis may be a valid molecular target in specific epithelial cancers. [This research was funded in part by NCI: P30 CA023074 & R03 CA230949.] Citation Format: Jessica Perer, Rebecca Justiniano, Anh Hua, Georg T. Wondrak. Zinc dysregulation as an emerging molecular target in epithelial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2665.