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Adenosine A 3 receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity
Author(s) -
Jajoo Sarvesh,
Mukherjea Debashree,
Watabe Kounosuke,
Ramkumar Vickram
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.524.17
Subject(s) - nadph oxidase , cancer research , metastasis , prostate cancer , rac1 , cancer cell , mapk/erk pathway , cancer , reactive oxygen species , biology , chemistry , kinase , medicine , microbiology and biotechnology , signal transduction
Prostate cancer metastasis is the major cause of mortality resulting from a lack of effective treatment. Studies have shown that the adenosine A 3 receptor (A 3 AR) suppresses proliferation of variety of tumors. However, their role in prostate tumor metastases is still not known. In the present study, we determined the effect of A 3 AR agonist N 6 ‐(3‐iodobenzyl) adenosine‐5′‐N‐methyluronamide (IB‐MECA) on prostate cancer cells invasion in vitro and metastasis in vivo . In severe combined immunodeficient (SCID) mice, IB‐MECA inhibited the metastases of AT6.1 rat prostate cancer cells. In vitro, IB‐MECA inhibited AT6.1 cells invasion by reducing high basal levels of reactive oxygen species (ROS) generation via NADPH oxidase. Furthermore, inhibition of Rac1 and p47 phox subunits of this enzyme by the dominant negative RacN17 or short interfering (si)RNA against p47 phox , reduced ROS generation and invasion of AT6.1 cells and inhibited the expression of p47 phox and Rac1 subunits. The inhibition of NADPH oxidase involves reduction in p47 phox translocation to the plasma membrane as a result of inhibition of extracellular signal‐regulated kinase (ERK)1/2‐dependent pathway. These results suggest that activation of A 3 AR in prostate cancer cells reduces ERK1/2‐dependent NADPH oxidase activity, which could account for reduced cancer cell invasiveness. This study was supported by a grant from SIU School of Medicine.