The effect of nitric oxide on cyclooxygenase-2 (COX-2) overexpression in head and neck cancer cell lines.
The overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been previously reported in head and neck squamous cell carcinoma (HNSCC), as well as in many cancers. We hypothesized that endogenous nitric oxide (NO) might increase the expression of COX-2 in cancer cells. Therefore, we investigated the cross-talk between NO and the prostaglandin (PG) pathways in HNSCC cell lines. We found that COX-2 and iNOS expressions were elevated simultaneously. On adding the NO donor, SNAP, the PGE2 level was increased 2-20 times due to increased COX-2 expression. This increase of COX-2 expression by SNAP or PMA (potent inducer of both iNOS and COX-2) was blocked to various degrees by NO scavengers and NOS inhibitors (L-NAME and 1400W). Also, the expression of COX-2 in resting cells was inhibited by NOS inhibitors. Moreover, COX-2 expression, induced by SNAP, was inhibited by ODQ, a soluble guanylate cyclase (sGC) inhibitor. The effect of dibutyryl-cGMP on COX-2 expression was similar to that of SNAP. These results imply that endogenous or exogenous NO activates sGC and that the resulting increase of cGMP induces a signaling that upregulates the expression of COX-2 in HNSCC cell lines. We also observed that NO increased COX-2 expression in different cancer cell lines, including cervic and gastric cancer cell lines. These findings further support the notion that NO can be associated with carcinogenesis through the upregulation of COX-2, and that NOS inhibitor may be also useful for cancer prevention.
Park
Seok-Woo
SW
Department of Tumor Biology, College of Medicine, Seoul National University, Seoul, Korea.
Lee
Sang-Goo
SG
Song
Sang-Hyun
SH
Heo
Dae-Seog
DS
Park
Bum-Jung
BJ
Lee
Dong-Wook
DW
Kim
Kwang-Hyun
KH
Sung
Myung-Whun
MW
D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003609:Dactinomycin / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D007527:Isoenzymes; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D003609:Dactinomycin; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate