Expression of cyclooxygenase-2 in uterine endometrial cancer and anti-tumor effects of a selective COX-2 inhibitor.
A role for cyclooxygenase-2 (COX-2) in the development and progression of various tumors has been identified. Selective COX-2 inhibitors produce anti-proliferative effects in various cancer cell lines that express COX-2. However, the mechanisms underlying anti-tumor effects are unclear. Furthermore, few studies have studied COX-2 expression in gynecological cancers, especially endometrial cancer. The current study had two goals. We investigated the correlation between COX-2 expression and clinicopathological factors of uterine endometrial cancer. We also investigated effects of treatment with etodolac, a selective COX-2 inhibitor, on the uterine endometrial cancer cell line TMG-L, which expresses COX-2. We conclusively confirmed expression of COX-2 mRNA and protein in endometrial cancer that exceeded levels of COX-2 seen in normal endometrium. However, no significant correlations were observed between COX-2 expression in endometrial cancer tumor samples and clinicopathological factors or disease-free survival rate of patients with endometrial cancer. Study of COX-2 inhibition of TMG-L cells showed that etodolac produced dose-dependent inhibition of cell proliferation through G1 phase cell-cycle arrest. Etodolac-induced cell-cycle arrest might be caused by increases in p53 and P21WAF1 protein expression. Production of basic-fibroblast growth factor (bFGF, a pro-angiogenesis factor) was inhibited by etodolac in a dose-dependent manner. Furthermore, telomerase activity was inhibited and expression of hTERT mRNA was significantly inhibited with etodolac, leading to the conclusion that anti-tumor effects of etodolac on TMG-L cells are due to inhibition of both angiogenesis and telomerase activity. These results strongly suggest that COX-2 inhibitors have potential as therapeutic (and possibly, chemopreventive) agents for endometrial cancers that overexpress COX-2.
Hasegawa
Kiyoshi
K
Department of Obstetrics and Gynecology, Fujita Health University School of Medicine, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan. khase@fujita-hu.ac.jp
Ohashi
Yoshimasa
Y
Ishikawa
Kunimi
K
Yasue
Akira
A
Kato
Rina
R
Achiwa
Yumiko
Y
Nishio
Eiji
E
Udagawa
Yasuhiro
Y
D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D018890:Chemoprevention; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D017308:Etodolac / Q000494:pharmacology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D016222:Fibroblast Growth Factor 2; D017308:Etodolac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases