Leptin induces functional activation of cyclooxygenase‐2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells

Hyperleptinemia is a common feature of obese women who have a higher risk of endometrial cancer than women with normal weights, and epidemiologic studies have suggested a correlation between obesity and endometrial carcinoma. Therefore, understanding of the molecular mechanism involved in leptin sig...

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Published in:Cancer science 2009-03, Vol.100 (3), p.389-395
Main Authors: Gao, Jingchun, Tian, Jianxin, Lv, Yunyi, Shi, Fangxin, Kong, Fandou, Shi, Hong, Zhao, Liyan
Format: Article
Language:English
Subjects:
Blotting, Western
Cell Line, Tumor
Cell Proliferation
Cyclooxygenase 2 - metabolism
Endometrial Neoplasms - metabolism
Endometrial Neoplasms - pathology
Enzyme Activation - physiology
Female
Humans
Immunoassay
Janus Kinase 2 - metabolism
Leptin - metabolism
Mitogen-Activated Protein Kinase Kinases - metabolism
Original
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Leptin - biosynthesis
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction - physiology
STAT3 Transcription Factor - metabolism
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Summary:Hyperleptinemia is a common feature of obese women who have a higher risk of endometrial cancer than women with normal weights, and epidemiologic studies have suggested a correlation between obesity and endometrial carcinoma. Therefore, understanding of the molecular mechanism involved in leptin signaling transduction is important in endometrial cancer prevention and treatment. In this study, both isoforms of the leptin receptor (Ob‐R), the long form (Ob‐Rb) and short form (Ob‐Ra), were detected as being expressed in six endometrial cancer cell lines with various differentiation status by western blotting, and Ob‐Ra was found to be more abundant than Ob‐Rb in these cells. Moreover, the expressions of both isoforms were inversely correlated with histoprognostic grading. We also showed that leptin stimulated cell proliferation and induced activations of signal transducers and activators of transcription 3 (STAT3), extracellular signal‐regulated kinase (ERK1/2), AKT, and cyclooxygenase (COX)‐2 in endometrial cancer cells dose‐dependently by [3H] thymidine incorporation assay and western blotting. Leptin‐stimulation resulted in increased expression of COX‐2 mRNA and prostaglandin E2 (PGE2) production of endometrial cancer cells by reverse transcription–polymerase chain reaction and enzyme immunoassay, respectively, which was effectively blocked by pharmacological inhibitors of Janus tyrosine kinase 2 (JAK2), AG490; of mitogen‐activated protein kinase (MAPK) kinase, U0126; of phosphatidylinositol 3‐kinase (PI3K), LY294002; and of COX‐2, NS398. These results suggest that leptin promotes cell proliferation of endometrial cancer cells via the aforementioned multiple signal‐transduction pathways. Leptin‐induced functional activation of COX‐2 is JAK2/STAT3‐, MAPK/ERK‐, and PI3K/AKT‐dependent, indicating that COX‐2 may be a critical factor of endometrial carcinogenesis in obesity. (Cancer Sci 2009; 100: 389–395)
ISSN:1347-9032
1349-7006
1349-7006
DOI:10.1111/j.1349-7006.2008.01053.x