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Nischarin is a scaffolding protein involved in the regulation of cell cytoskeletal organization and metabolic homeostasis. In breast and ovarian cancers, nischarin has been demonstrated to have tumor suppressive functions. We have found that nischarin was expressed in both the epithelial and stromal compartments of the PDAC patient tissue, in cancer cell lines and patient-derived stellate cells. Of interest, nischarin is a functional imidazoline 1 receptor for which there are several FDA-approved agonists used for treatment of hypertension. The aim of this study was to examine the effects of nischarin agonists on PDAC cancer cells and stellate cells, separately and in co-culture and determine the potential for their repurposing in treatment of PDAC. mRNA sequencing revealed that cancer cell treatment with nischarin agonist rilmenidine induced transcriptional changes associated with regulation of cell adhesion, EMT and vesicular transport. In vitro, rilmenidine treatment of cancer cells decreased their migration and invasion potential and treatment of stellate cells decreased the αSMA-positive fraction. Treatment of cancer cell-stellate cell co-cultures decreased the production of pro-inflammatory cytokines IL-6, IL-8 and CCL-2, known drivers of the metastatic progression. Ultimately, rilmenidine treatment decreased PDAC cell invasion in Tg(fli1: EGFP) zebrafish model. Taken together, nischarin agonist rilmenidine has a potential for limiting the processes involved in PDAC metastatic cascade and may be a good candidate for drug repurposing. Citation Format: Jelena Grahovac, Kristina Živić, Marijana Pavlović, Marija Ostojić, Ana Đurić, Tatjana Srdić-Rajić, Aleksandar Pavić, Danijel Galun. Nischarin is a potential druggable target in both epithelial and stromal compartments of pancreatic ductal adenocarcinoma [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 2476. |
