MutY-Homolog (MYH) inhibition reduces pancreatic cancer cell growth and increases chemosensitivity

// George Sharbeen 1 , Janet Youkhana 1 , Amanda Mawson 1 , Joshua McCarroll 2, 3 , Andrea Nunez 1 , Andrew Biankin 4, 5 , Amber Johns 5 , David Goldstein 1 , Phoebe Phillips 1, 3 1 Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia 2 Children’s Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia 3 Australian Centre for NanoMedicine, University of New South Wales, Sydney, Australia 4 Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Bearsden, Glasgow, Scotland, United Kingdom 5 The Kinghorn Cancer Centre, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia Correspondence to: Phoebe Phillips, email: p.phillips@unsw.edu.au Keywords: pancreatic cancer, mutY-homolog (MYH), chemoresistance, oxidative stress, DNA repair Received: February 08, 2016      Accepted: December 12, 2016      Published: December 16, 2016 ABSTRACT Patients with pancreatic ductal adenocarcinoma (PC) have a poor prognosis due to metastases and chemoresistance. PC is characterized by extensive fibrosis, which creates a hypoxic microenvironment, and leads to increased chemoresistance and intracellular oxidative stress. Thus, proteins that protect against oxidative stress are potential therapeutic targets for PC. A key protein that maintains genomic integrity against oxidative damage is MutY-Homolog (MYH). No prior studies have investigated the function of MYH in PC cells. Using siRNA, we showed that knockdown of MYH in PC cells 1) reduced PC cell proliferation and increased apoptosis; 2) further decreased PC cell growth in the presence of oxidative stress and chemotherapy agents (gemcitabine, paclitaxel and vincristine); 3) reduced PC cell metastatic potential; and 4) decreased PC tumor growth in a subcutaneous mouse model in vivo . The results from this study suggest MYH may be a novel therapeutic target for PC that could potentially improve patient outcome by reducing PC cell survival, increasing the efficacy of existing drugs and reducing metastatic spread.