
4‐(Methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro
Author(s) -
Shin Vivian Y.,
Jin Hong C.,
Ng Enders K. O.,
Cho Chi H.,
Leung Wai K.,
Sung Joseph J. Y.,
Chu KentMan
Publication year - 2011
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.01885.x
Subject(s) - prostaglandin e2 receptor , downregulation and upregulation , angiogenesis , carcinogenesis , cancer research , chemistry , cell growth , prostaglandin , cyclin d1 , cancer , endocrinology , medicine , receptor , cell cycle , biology , biochemistry , gene , agonist
Prostaglandin E (EP) receptor is positively related with COX‐2, which is involved in cancer biology. A mechanistic study on how 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) promotes gastric carcinogenesis is lacking. Recently, we found that nicotine promoted tumor growth through upregulation of the COX‐2/prostaglandin E 2 pathway. This extended our study on the involvement of EP receptors in gastric carcinogenesis. Both in vitro and in vivo studies showed that NNK promoted cancer cell growth with concomitant EP2 and EP4 upregulation. We found that NNK stimulated vascular endothelial growth factor (VEGF) and angiogenesis, but suppressed apoptosis by increasing Bcl2 and decreasing caspase‐3 expressions. Both EP2 and EP4 siRNA significantly impaired these tumorigenic actions of NNK in xenograft tumor. Cell cycle analysis showed that NNK increased S phase entry with increased cyclin D1 and the associated cyclin‐dependent kinase 4/6, and downregulation of p21 and p27. The p38 phosphorylation was EP2/4‐dependent, and SB203580 (p38 inhibitor) suppressed NNK‐induced prostaglandin E 2 , VEGF, and cell proliferation. Antagonists of EP2 or EP4 abolished the elevated VEGF and VEGF receptor‐2. These data strongly indicate that EP2/4 are important for NNK‐promoted gastric carcinogenesis, thus providing a framework for future evaluation of EP antagonist(s) as anticancer drugs for smokers. ( Cancer Sci 2011; 102: 926–933)