Jessica Perer Abstracts
Jessica Perer
Ph.D. Candidate
Cancer Biology GIDP
American Association for Cancer Research
Atlanta, Georgia
March 29-31, 2019
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.]
Abstract for Lay Audience
Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States. NMSC incidences are increasing rapidly, presenting a public health burden of considerable magnitude. Various causative factors involved in NMSC have been identified including sunlight (UV) exposure, and human papilloma virus (HPV) infection. High incidence of NMSC combined with poor prognosis associated with metastatic progression, demand the development of novel strategies targeting the disease, particularly in early stages. Recent evidence in our lab has begun to identify additional causative factors in NMSC progression, in which depleted cellular zinc levels were established. Zinc is an essential element required for normal immune system and metabolism function. Therefore, zinc depletion can cause a variety of adverse health effects such as diabetes, and chronic liver and renal disease. Zinc transport is highly regulated within the human body and is achieved by a family of zinc cellular importers (ZIPs), in which zinc depletion occurs downstream of ZIP protein downregulation. For example, our lab confirmed zinc and ZIP depletion in NMSC. Therefore, by pharmacologically increasing cellular zinc, we can target zinc vulnerabilities for chemotherapeutic intervention. In order to increase cellular zinc, current research in our lab focuses on an FDA-approved over the counter agent, zinc pyrithione (ZnPT), proven effective in targeting NMSC. We then aimed to expand zinc vulnerabilities present in skin cancer and explore additional epithelial malignancies, such as pancreatic cancer. Pancreatic cancer has the highest mortality in the United States of all cancer types. As compared to NMSC, there exists an urgent need to develop novel treatment options. Likewise, our lab was able to determine similar vulnerabilities exist in pancreatic cancer, in which cancer cells demonstrated lower zinc and ZIP protein levels. Furthermore, by increasing cellular zinc concentration by ZnPT, we were able to kill pancreatic cancer cells. Based on these prototype observations and the safety of ZnPT, we then validated ZnPT-induced NMSC suppression in mouse skin. We are currently determining whether pharmacological disruption of cancer cell zinc homeostasis will offer novel molecular opportunities for pancreatic cancer chemoprevention. Finally, ZIP downregulation and ZnPT induction of zinc overload will provide an efficacious chemotherapeutic to target zinc-depleted epithelial cancers.