Abstract 3667: Potential role of DUSP4 as a tumor suppressor in pancreatic cancer

Abstract

Abstract Pancreatic cancer remains one of the most lethal of all human malignancies, with 48,960 expected new cases and 40,560 deaths predicted in the USA in the year 2015. In order to develop novel strategies for the management of pancreatic cancer, it is of utmost importance to intensify our efforts to dissect the molecular mechanisms involved in the pathophysiology of this fatal neoplasm. Dual-specificity phosphatase-4 (DUSP4), a family member of dual-specificity phosphatases, is capable of dephosphorylating both phosphotyrosine and phosphoserine/phosphothreonine residues and possesses activity against key signaling components of the MAPK pathway that plays an important role in cancer growth. DUSP4 has been shown to be widely expressed in different tissues and implicated in cancer development, differentiation, apoptosis and inflammation. In a recent study from our laboratory that was aimed at defining the molecular targets of the anti-cancer plant-based alkaloid sanguinarine in pancreatic cancer, we identified DUSP4 as a key protein modulated by sanguinarine. Specifically, based on proteomics data and validation by qRT-PCR and immunoblot analysis, we found that sanguinarine significantly increases DUSP4 in BxPC-3 and MIA PaCa-2 pancreatic cancer cells. Indeed, an association of DUSP4 loss with cancer progression has been shown in certain cancers. However, the role of DUSP4 in pancreatic cancer is not known. This study was designed to determine the role and importance of DUSP4 in pancreatic cancer. We determined the expression profile of DUSP4 in pancreatic cancer using immunohistochemical analysis of a tissue microarray containing a variety of pancreatic cancers and normal pancreatic tissues. The DUSP4-immunostaining was microscopically imaged followed by quantification of DUSP4 protein by multispectral Vectra™ system coupled with inForm software. We found a significant downregulation of DUSP4 in human pancreatic cancer tissues, when compared to normal pancreatic tissues. Further, to understand the importance of DUSP4 in pancreatic cancer, we determined the effect of a force overexpression of DUSP4 in MIA PaCa-2 pancreatic cancer cells. We found that DUSP4 overexpression in MIA PaCa-2 cells resulted in a significant i) decrease in cell growth and proliferation, ii) clonogenic survival, and iii) induction of apoptosis. These preliminary findings suggest a potential tumor suppressive function of DUSP4 in pancreatic cancer. Further detailed studies are ongoing in our laboratory to validate the role and functional significance of DUSP4 in pancreatic cancer. Citation Format: Chandra K. Singh, Jasmine George, Minakshi Nihal, Nihal Ahmad. Potential role of DUSP4 as a tumor suppressor in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3667.