Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death

Free Radic Biol Med. 2016 Oct:99:593-607. doi: 10.1016/j.freeradbiomed.2016.08.019. Epub 2016 Sep 12.

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.

Keywords: Autophagy; Cell death; G2/M; Natriuretic peptide receptor A; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Anthracenes / pharmacology
  • Atrial Natriuretic Factor / genetics
  • Atrial Natriuretic Factor / metabolism
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • G2 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Imidazoles / pharmacology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Nude
  • Neoplasm Staging
  • Pyridines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / agonists*
  • Reactive Oxygen Species / metabolism
  • Receptors, Atrial Natriuretic Factor / antagonists & inhibitors*
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / metabolism
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anthracenes
  • Imidazoles
  • Pyridines
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • pyrazolanthrone
  • 3-methyladenine
  • Atrial Natriuretic Factor
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A
  • Adenine
  • SB 203580
  • Acetylcysteine