COX-2 specific inhibitor, NS-398, increases macrophage migration inhibitory factor expression and induces neuroendocrine differentiation in C4-2b prostate cancer cells.
BACKGROUND
Cyclooxygenase-2 (COX-2) is an inducible enzyme involved in the conversion of arachadonic acid to prostaglandins and other eicosaniods. Persistent COX-2 expression is associated with multiple forms of cancer.Therefore, there is much interest in COX-2 specific, non-steroidal anti-inflammatory drug use for cancer chemotherapy. The mechanism by which these drugs inhibit tumor growth and progression is unclear, and our knowledge about their potential to prevent or treat prostate cancer is inadequate.


METHODS
The effects of NS-398, a selective COX-2 inhibitor, on human prostate carcinoma cell line LNCaP and the LNCaP subline C4-2b were investigated in this study. NS-398 effects on apoptosis were examined by caspase-3 activity increase, as well as internucleosomal cleavage. ELISA and PCR were used to determine inhibitor effects on macrophage migration inhibitory factor (MIF) and COX-2 production.


RESULTS
At 10 microM, NS-398 treatment resulted in increased production of COX-2 and the pro-inflammatory cytokine, MIF by the C4-2b LNCaP subline. NS-398 (10 microM) induces apoptosis in LNCaP cells, but not in the more aggressive, androgen-unresponsive C4-2b cells. The C4-2b cells were observed to continue to proliferate when treated with NS-398 and continued to retain malignant phenotype characteristics. NS-398 treatment resulted in C4-2b cell differentiation into an unusual neuroendocrine-like cell. These neuroendocrine-like cells produced both epithelial (cytokeratin 18 and prostate specific antigen) and neuronal (neuron-specific enolase and chromogranin A) proteins. Furthermore, this C4-2b cellular response to NS-398 was mediated by NF-kappa beta transcription factor activation.


CONCLUSIONS
These data suggest that COX-2 inhibition induces NF-kappa beta transcription factor activation, which subsequently induces pro-inflammatory protein expression (COX-2 and MIF) and neuroendocrine differentiation in the LNCaP C4-2b subline. These data provide further evidence that pro-inflammatory protein expression may play an important role in prostate cancer progression.
Meyer-Siegler
K
K
Department of Research and Development, Bay Pines Veteran's Administration Medical Center, FL 33744, USA. ksiegler@hsc.usf.edu
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002454:Cell Differentiation; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020672:I-kappa B Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis; D009578:Nitrobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000072000:NF-KappaB Inhibitor alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases