Loss of TNF-alpha-regulated COX-2 expression in ovarian cancer cells.
Cyclooxygenase 2 (COX-2) is often found overexpressed in cancer and is thought to have a role in carcinogenic promotion, and thus is a target for therapeutic intervention. Here, we investigated the regulation of COX-2 expression in normal and cancer ovarian surface epithelial cells. Tumor necrosis factor alpha (TNF-alpha) is a potent inducer of COX-2 expression in the ovarian surface epithelium and this regulation is a critical step in ovulation. We observed that TNF-alpha stimulated COX-2 expression in human primary and immortalized epithelial (HIO) cell lines. The stimulation was suppressed by inhibitors of several signaling pathways, indicating the collaboration of TNF-alpha-activated signaling pathways mediates the regulation of COX-2 expression. In five ovarian cancer cell lines analysed, four did not express detectable COX-2 and TNF-alpha failed to elicit COX-2 expression. In NIH:OVCAR-5, the only ovarian cancer cell line expressing COX-2, signal pathway inhibitors no longer affected TNF-alpha-induced COX-2 expression. Thus, we conclude that TNF-alpha mediated signaling is uncoupled from the modulation of COX-2 expression in ovarian cancer. The loss of COX-2 expression was also observed to associate closely with epithelial neoplastic morphological transformation. The frequent loss of COX-2 expression suggests in ovarian cancer, unlike in other epithelial cancers, COX-2 expression does not contribute to ovarian cancer malignancy.
Yang
Wan-Lin
WL
Ovarian Cancer and Tumor Cell Biology Programs, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Roland
Isabelle H
IH
Godwin
Andrew K
AK
Xu
Xiang-Xi
XX
D015153:Blotting, Western; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human