title: MutY-Homolog (MYH) inhibition reduces pancreatic cancer cell growth and increases chemosensitivity.
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.
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Sharbeen
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Janet
authors.initials: J
authors.lastname: Youkhana
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mawson
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.|Australian Centre for NanoMedicine, University of New South Wales, Sydney, Australia.
authors.forename: Joshua
authors.initials: J
authors.lastname: McCarroll
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nunez
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Bearsden, Glasgow, Scotland, United Kingdom.|The Kinghorn Cancer Centre, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Biankin
authors.affiliation: The Kinghorn Cancer Centre, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia.
authors.forename: Amber
authors.initials: A
authors.lastname: Johns
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
authors.affiliation: Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.|Australian Centre for NanoMedicine, University of New South Wales, Sydney, Australia.
authors.forename: Phoebe
authors.initials: P
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018384:Oxidative Stress / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment; D014750:Vincristine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D014750:Vincristine; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D017239:Paclitaxel; D000093542:Gemcitabine
keywords: DNA repair; chemoresistance; mutY-homolog (MYH); oxidative stress; pancreatic cancer