RRC ID 17687
著者 Shin VY, Jin HC, Ng EK, Cho CH, Leung WK, Sung JJ, Chu KM.
タイトル 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro.
ジャーナル Cancer Sci
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.
巻・号 102(5)
ページ 926-33
公開日 2011-5-1
DOI 10.1111/j.1349-7006.2011.01885.x
PMID 21261791
MeSH Animals Blotting, Western Carcinogens / toxicity* Cell Line, Tumor Cell Proliferation / drug effects Enzyme-Linked Immunosorbent Assay Humans Immunohistochemistry Mice Mice, Nude Nitrosamines / toxicity* Receptors, Prostaglandin E, EP2 Subtype / metabolism* Receptors, Prostaglandin E, EP4 Subtype / metabolism* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Stomach Neoplasms / chemically induced Stomach Neoplasms / metabolism* Xenograft Model Antitumor Assays
IF 4.966
引用数 10
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 MKN45(RCB1001)