title: Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death.
abstract: Natriuretic peptide receptor A (NPRA), the major receptor for atrial natriuretic peptide (ANP), has been implicated in tumorigenesis; however, the role of ANP-NPRA signaling in the development of gastric cancer remains unclear. Immunohistochemical analyses indicated that NPRA expression was positively associated with gastric tumor size and cancer stage. NPRA inhibition by shRNA induced G2/M cell cycle arrest, cell death, and autophagy in gastric cancer cells, due to accumulation of reactive oxygen species (ROS). Either genetic or pharmacologic inhibition of autophagy led to caspase-dependent cell death. Therefore, autophagy induced by NPRA silencing may represent a cytoprotective mechanism. ROS accumulation activated c-Jun N-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). ROS-mediated activation of JNK inhibited cell proliferation by disturbing cell cycle and decreased cell viability. In addition, AMPK activation promoted autophagy in NPRA-downregulated cancer cells. Overall, our results indicate that the inhibition of NPRA suppresses gastric cancer development and targeting NPRA may represent a promising strategy for the treatment of gastric cancer.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Wei-Zhi
authors.initials: WZ
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhi
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Bo-Wen
authors.initials: BW
authors.lastname: Li
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Lin-Jun
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Xie
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jin-Qiu
authors.initials: JQ
authors.lastname: Tao
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Dian-Cai
authors.initials: DC
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. Electronic address: xuzekuan@njmu.edu.cn.
authors.forename: Ze-Kuan
authors.initials: ZK
authors.lastname: Xu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000873:Anthracenes; D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C432165:pyrazolanthrone; C025946:3-methyladenine; D009320:Atrial Natriuretic Factor; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D000225:Adenine; C093642:SB 203580; D000111:Acetylcysteine
keywords: Autophagy; Cell death; G2/M; Natriuretic peptide receptor A; Reactive oxygen species