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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
Author(s) -
Yu Le,
Wu William Ka Kei,
Li Zhi Jie,
Li Hai Tao,
Wu Ya Chun,
Cho Chi Hin
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24607
Subject(s) - extracellular , protein kinase a , cancer research , kinase , protein kinase c , signal transduction , microbiology and biotechnology , cell growth , cyclin dependent kinase 2 , prostaglandin , cell , biology , chemistry , endocrinology , biochemistry
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. © 2009 UICC