Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma.
- Resource Type
- Academic Journal
- Authors
- Zarei M; Department of Surgery, University Hospitals; Case Western University, School of Medicine, Cleveland, OH.; Shrestha R; Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX.; Johnson S; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX.; Yu Z; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX.; Henan University of Science and Technology, Luoyang, Henan Province, China, P.R.; Karki K; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX.; Vaziri-Gohar A; Department of Surgery, University Hospitals; Case Western University, School of Medicine, Cleveland, OH.; Epps J; Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX.; Du H; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; Suva L; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX.; Zarei M; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX.; Safe S; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX.
- Source
- Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9918281580506676 Publication Model: Print Cited Medium: Internet ISSN: 2767-9764 (Electronic) Linking ISSN: 27679764 NLM ISO Abbreviation: Cancer Res Commun
- Subject
- Language
- English
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemotherapy with gemcitabine has limited effects and is associated with development of drug resistance. Treatment of Panc1 and MiaPaca2 pancreatic cancer cells with gemcitabine induced expression of the orphan nuclear receptor 4A2 (NURR1) and analysis of the cancer genome atlas indicated the NURR1 is overexpressed in pancreatic tumors and is a negative prognostic factor for patient survival. Results of NURR1 knockdown or treatment with the NURR1 antagonist 1,1-bis(3΄-indolyl)-1-(p-chlorophenyl)methane (C-DIM 12) demonstrated that NURR1 was pro-oncogenic in pancreatic cancer cells and regulated cancer cell and tumor growth and survival. NURR1 is induced by gemcitabine and serves as a key drug-resistance factor and is also required for gemcitabine-induced cytoprotective autophagy. NURR1 regulated genes were determined by RNA sequencing of mRNAs expressed in MiaPaCa2 cells expressing NURR1 and in CRISPR/Cas9 gene edited cells for NURR1 knockdown and KEGG enrichment analysis of the differentially expressed genes showed that autophagy was the major pathway regulated by NURR1. Moreover, NURR1 regulated expression of two major autophagic genes ATG7 and ATG12 which are also overexpressed in pancreatic tumors and like NURR1 are negative prognostic factors for patient survival. Thus, gemcitabine-induced cytoprotective autophagy is due to the NURR1 - ATG7/ATG12 axis and this can be targeted and disrupted by NURR1 antagonist C-DIM12 demonstrating the potential clinical applications for combination therapies with gemcitabine and NURR1 antagonists.
Competing Interests: Disclosure of Conflicts of Interest: There are no other conflicts of interests to declare.