Role and Mechanism of Cyclooxygenase-2 in Oral arcinogenesis
Date Issued
2005
Date
2005
Author(s)
Chang, Jen-Kuan
DOI
en-US
Abstract
Cyclooxygenase-2 (COX-2) is the inducible form of the COX enzymes, it has been shown to overexpress in a variety of human malignancies. COX-2 catalyzes synthesis of prostaglandins (PGs) with diversified biological activities, and its dysregulation plays a vital role in inflammation, tissue damage, and tumorigenesis. Previously studies show that the COX-2 is involved in the early stages of the oncogenic process of colorectal tumors, and a great amount of evidence also suggests COX-2 upregulation is close associated with tumor invasion and metastasis. But some other reports point out that COX-2 overexpression may induce tumor suppressor protein p53 upregulation, and led to cell cycle arrest. Previous study showed that areca nut extract can induce COX-2 secretion in KB cells. The aim of this study is to investigate the possible role of COX-2 in oral carcinogenesis.
We transfected COX-2 expression vectors into human oral cancer SAS cells and successfully obtained clones with COX-2 overexpression (SAS/COX-2 c.2/5/6). Tumorigenesis assay showed that COX-2 transfected clones formed tumors in SCID mice more rapidly than the control cells. These tumors appeared to be highly vascularized using pathological examination. Immunoblot analysis showed that Bcl-2, an anti-apoptotic protein, was specifically up-regulated COX-2 transfectants but not in the control cells. The use of pharmacological inhibitors or activators revealed that prostaglandin EP(2) receptor but not other prostaglandin receptors is involved in COX-2-mediated Bcl-2 up-regulation. We also for the first time to show COX-2 can induce the expression of another anti-apoptotic protein ferritin heavy chain and the induction is through PGE2-independent manner. Furthermore, SAS/COX-2 cells, but not vector control cells, were resistant to cisplatin-induced cytotoxicity. These results suggest that overexpression of COX-2 enhances the tumorigenic activity of oral cancer cells by both suppressing apoptosis and actively promoting angiogenesis.
Celecoxib, a cyclooxygenase 2 inhibitor, has chemopreventive and therapeutic activities toward many epithelial malignancies. Celecoxib can induce apoptosis in various cancer cell lines through a mechanism that is independent of its cyclooxygenase 2 inhibitory activity but its effects on oral cancer cells is largely uncharacterized. We found celecoxib significantly inhibited the proliferation of SAS and CA9-22 oral cancer cell line in a dose-dependent manner with a 50% inhibition concentration (IC50) of celecoxib is 50uM. DNA flow cytometric analysis showed that Celecoxib treatment induces G1 phase arrest. Celecoxib treatment also caused significant apoptosis of SAS and CA9-22 cells as evidenced by Hoechst 33258 staining, DNA fragmentation and cleavage of PARP. Celecoxib treatment induced the expression of death receptors, particularly that of DR5. It seems celecoxib activates extrinsic apoptosis pathway.
Subjects
環氧化酵素二型
前列腺素E2
癌化
希樂葆
COX-2
PGE2
carcinogenesis
celecoxib
SDGs
Type
other
File(s)![Thumbnail Image]()
Loading...
Name
ntu-94-R92450003-1.pdf
Size
23.31 KB
Format
Adobe PDF
Checksum
(MD5):1fbe21d4f3da90860c85dda377601e46