Abstract
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. 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. 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. 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.
Highlights
In the United States, prostate cancer is the most common malignancy and second leading cancer-related death cause in males
Among the various pro-inflammatory proteins recently investigated, COX-2 up-regulation is a frequent occurrence in a variety of tumors including the prostate [4,22,23]
A recent study has determined that COX-2 expression is 4 fold and migration inhibitory factor (MIF) neutralizing antibody (1:200 dilution)
Summary
In the United States, prostate cancer is the most common malignancy and second leading cancer-related death cause in males. Current metastatic prostate cancer treatment is based on androgen ablation, which initially results in reduced tumor cell growth, apoptosis and temporary symptom regression. This treatment modality usually results in aggressive androgen-unresponsive relapse that is resistant to further hormonal manipulation or conventional chemotherapy. Conclusions: These data suggest that COX-2 inhibition induces NF- 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
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