4‐(Methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro

Abstract

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) C igarette smoking is the most preventable cause of cancer death, contributes to 30% of all cancer deaths in USA, (1) and is one of the risk factors for gastric cancer. A meta-analysis showed that the risk of gastric cancer increased by 60% in male and 20% in female smokers.(2) The risk of gastric cancer increased with cumulative dose of cigarette smoke, hence smokers have double the risk of gastric cancer than non-smokers. Evidence shows that smokers not only have a poorer prognosis, but also more advanced disease at the time of diagnosis than non-smokers. It has been shown that smokers augmented the risk of gastric cancer from gastric atrophy, compared to nonsmokers.(4) Carcinogens in cigarette smoke can cause DNA damage and mutation (K-ras and p53), or elicit a cascade of events leading to tumorigenesis of various malignancies. These findings put forward the hypothesis that the conduit for cancer development and progression is different among smokers and non-smokers. Poor survival rate is due to lower response rates to chemotherapy ⁄ radiation during cancer treatment. (6,7) 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a well-known potent animal carcinogen in cigarette smoke causing various types of cancers, including gastric cancer.(8) Hence, better understanding of smoking-induced cellular and molecular changes would be helpful for the development of effective therapeutic strategies for gastric cancer.Prostaglandin E 2 (PGE 2 ) is produced in gastric tissue with various physiologic and pathologic functions. It was produced in normal epithelial cells and at high levels in tumor ...

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