Prostaglandin E(2) promotes cell proliferation via protein kinase C/extracellular signal regulated kinase pathway-dependent induction of c-Myc expression in human esophageal squamous cell carcinoma cells.
Overexpression of cyclooxygenase-2 (COX-2) and elevation of its derivative prostaglandin E(2) (PGE(2)) are implicated in human esophageal squamous cell carcinoma. The expression of c-Myc, an oncogenic transcription factor, is also upregulated in this malignant disease. This study sought to elucidate whether a functional connection exists between COX-2/PGE(2) and c-Myc in esophageal squamous cell carcinoma. Results showed that PGE(2) substantially increased the proliferation of cultured esophageal squamous cell carcinoma cells. In this regard, PGE(2) substantially increased the mRNA and protein expression of c-Myc and its association with the binding partner Max. Knockdown of c-Myc by RNA interference also significantly attenuated PGE(2)-induced cell proliferation. Further, mechanistic study revealed that PGE(2) increased the protein stability and nuclear accumulation of c-Myc via phosphorylation on serine 62 in an extracellular signal regulated kinase (ERK)-dependent manner. To this end, ERK activation by PGE(2) was completely abolished by protein kinase C (PKC) inhibitors. Moreover, the effect of PGE(2) on c-Myc expression was mimicked by EP2 receptor agonist. In addition, knockdown of EP2 receptor by EP2 siRNA attenuated PGE(2)-induced c-Myc expression. Collectively, our findings suggest that PGE(2) upregulates c-Myc via the EP2/PKC/ERK pathway. This study sheds new light on the carcinogenic mechanism of PGE(2) in esophageal squamous cell carcinoma.
Yu
Le
L
Department of Pharmacology, The Chinese University of Hong Kong, Hong Kong, China.
Wu
William Ka Kei
WK
Li
Zhi Jie
ZJ
Li
Hai Tao
HT
Wu
Ya Chun
YC
Cho
Chi Hin
CH
D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D010120:Oxytocics / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C489427:MYC protein, human; D010120:Oxytocics; C545644:PTGER2 protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone