Celecoxib-induced growth inhibition in SW480 colon cancer cells is associated with activation of protein kinase G.

Jae-Won Soh, Julhash U Kazi, Han Li, W Joseph Thompson, I Bernard Weinstein

Biomedical Research Center for Signal Transduction Networks, Department of Chemistry, Inha University, Incheon, Korea.

Molecular carcinogenesis 2008 Jul

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Although it is often assumed that the antitumor effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to inhibition of cyclooxgenase (COX) activity, specifically COX-2, there is accumulating evidence that COX-2 independent mechanisms can also play an important role. Studies with sulindac sulfone (Aptosyn) and related derivatives have revealed a novel pathway of tumor growth inhibition and apoptosis mediated by activation of the guanosine 3',5' monophosphate (cGMP)-dependent enzyme protein kinase G (PKG). The present study indicates that concentrations of the NSAIDs celecoxib, indomethacin, and meclofenamic acid that inhibit growth of SW480 human colon cancer cells inhibit subcellular cGMP-phosphodiesterase (PDE) enzymatic activity and in intact cells induce a two- to threefold increase in intracellular levels of cGMP. This is associated with phosphorylation of the protein VASP, a marker of PKG activation, activation of JNK1 and a decrease in cellular levels of cyclin D1; effects seen with other agents that cause activation of PKG in these cells. On the other hand even a high concentration of the COX-2 specific inhibitor rofecoxib (500 microM) did not inhibit growth of SW480 cells. Nor did rofecoxib inhibit cGMP-PDE activity or cause other changes related to PKG activation in these cells. Since activation of the PKG pathways by celecoxib, indomethacin, and meclofenamic acid in this cell culture system required high concentrations of these compounds, it remains to be determined whether activation of this pathway contributes to the in vivo antitumor effects of specific NSAIDs. Copyright 2007 Wiley-Liss, Inc.

Citation

Jae-Won Soh, Julhash U Kazi, Han Li, W Joseph Thompson, I Bernard Weinstein. Celecoxib-induced growth inhibition in SW480 colon cancer cells is associated with activation of protein kinase G. Molecular carcinogenesis. 2008 Jul;47(7):519-25