4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro.
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.
Department of Surgery, The University of Hong Kong, Hong Kong.
Vivian Y
VY
Shin
Hong C
HC
Jin
Enders K O
EK
Ng
Chi H
CH
Cho
Wai K
WK
Leung
Joseph J Y
JJ
Sung
Kent-Man
KM
Chu
D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009602:Nitrosamines / Q000633:toxicity*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D002273:Carcinogens; D009602:Nitrosamines; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone