Natriuretic peptide receptor a as a novel anticancer target

Cancer Res. 2008 Jan 1;68(1):249-56. doi: 10.1158/0008-5472.CAN-07-3086.


The receptor for atrial natriuretic peptide (ANP), natriuretic peptide receptor A (NPRA), is expressed in cancer cells, and natriuretic peptides have been implicated in cancers. However, the direct role of NPRA signaling in tumorigenesis remains elusive. Here, we report that NPRA expression and signaling is important for tumor growth. NPRA-deficient mice showed significantly reduced antigen-induced pulmonary inflammation. NPRA deficiency also substantially protected C57BL/6 mice from lung, skin, and ovarian cancers. Furthermore, a nanoparticle-formulated interfering RNA for NPRA attenuated B16 melanoma tumors in mice. Ectopic expression of a plasmid encoding NP73-102, the NH(2)-terminal peptide of the ANP prohormone, which down-regulates NPRA expression, also suppressed lung metastasis of A549 cells in nude mice and tumorigenesis of Line 1 cells in immunocompetent BALB/c mice. The antitumor activity of NP73-102 was in part attributed to apoptosis of tumor cells. Western blot and immunohistochemistry staining indicated that the transcription factor, nuclear factor-kappaB, was inactivated, whereas the level of tumor suppressor retinoblastoma protein was up-regulated in the lungs of NPRA-deficient mice. Furthermore, expression of vascular endothelial growth factor was down-regulated in the lungs of NPRA-deficient mice compared with that in wild-type mice. These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Apoptosis
  • Cell Transformation, Neoplastic / genetics
  • Female
  • Guanylate Cyclase / antagonists & inhibitors
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / physiology*
  • Inflammation / genetics
  • Inflammation / pathology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • NF-kappa B / metabolism
  • Nanoparticles / therapeutic use
  • Neoplasms / blood supply*
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / genetics*
  • Ovarian Neoplasms / genetics
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Atrial Natriuretic Factor / antagonists & inhibitors
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / physiology*
  • Retinoblastoma Protein / metabolism
  • Skin Neoplasms / genetics
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism


  • NF-kappa B
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • Vascular Endothelial Growth Factor A
  • Guanylate Cyclase
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A