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COX-2 Specific Inhibitor, NS-398, Increases Macrophage Migration Inhibitory Factor Expression and Induces Neuroendocrine Differentiation in C4-2b Prostate Cancer Cells

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Abstract

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.

Materials and 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 µM, 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 µM) 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 neuroendocrinelike 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-κβ transcription factor activation.

Conclusions

These data suggest that COX-2 inhibition induces NF-κβ 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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Acknowledgements

This material is based upon work supported by the Office of Research and Development and the Medical Research Service, Department of Veterans Affairs. The author would like to thank W. Webster, Pharm. D. and M. Tannenbaum, M.D. for their critical review of the manuscript.

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Authors and Affiliations

  1. Department of Research and Development, Bay Pines Veteran’s Administration Medical Center, Bay Pines, FL, USA

    Katherine Meyer-Siegler

  2. Department of Surgery, University of South Florida College of Medicine, Tampa, FL, USA

    Katherine Meyer-Siegler

  3. P.O. Box 5005, Bay Pines, FL, 33744, USA

    Katherine Meyer-Siegler

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Correspondence to Katherine Meyer-Siegler.

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Meyer-Siegler, K. COX-2 Specific Inhibitor, NS-398, Increases Macrophage Migration Inhibitory Factor Expression and Induces Neuroendocrine Differentiation in C4-2b Prostate Cancer Cells. Mol Med 7, 850–860 (2001). https://doi.org/10.1007/BF03401977

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  • DOI: https://doi.org/10.1007/BF03401977

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