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Induction of Cell Death in Pancreatic Tumors by Zinc and Its Fluorescence Chelator TSQ

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Abstract

Pancreatic ductal adenocarcinoma is a devastating cancer and is the fourth-leading cause of cancer death in the USA. Zinc is abundant in the pancreas, but its role in pancreatic cancer remains elusive. The aim of this study is to determine effects of zinc chelators in pancreatic cancer. Pdx1Cre and LSL-KrasG12D mice expressing an oncogenic mutation of KRAS develop pancreatic intraepithelial neoplasia in the pancreas. We found that EPCAM + tumors developed in the mouse pancreas store zinc that is detectable by fluorescence-activated cell sorting using N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide (TSQ), a fluorescence chelator. EPCAM + TSQ + tumor cells isolated from the mouse pancreas formed organoids in matrigel. Upon treatment with N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), a zinc chelator, the organoids degenerated and its negative effect was rescued by co-treatment with zinc, indicating that zinc is necessary for the growth and survival of tumor organoids. Different from TPEN, TSQ treatment did not affect the organoid growth and survival. Interestingly, co-treatment with TSQ and zinc resulted in strong emission of TSQ fluorescence in the organoid and its degeneration. The combination of zinc with TSQ, but not with TPEN, also induced cell death in PANC-1, a human pancreatic cancer cell line. These results suggest that a TSQ-zinc complex formed in pancreatic tumors induces cell death if zinc is overloaded.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by the pilot project from the Southern California Research Center for ALPD & Cirrhosis (National Institutes of Health P50AA11999) and USC Dean’s pilot project program.

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  1. The Southern California Research Center for ALPD & Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, 1333 San Pablo St., MMR 402, Los Angeles, CA, 90033, USA

    Kinji Asahina

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Asahina, K. Induction of Cell Death in Pancreatic Tumors by Zinc and Its Fluorescence Chelator TSQ. Biol Trace Elem Res 200, 1667–1676 (2022). https://doi.org/10.1007/s12011-021-02770-7

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