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Activation of Protein Kinase G Is Sufficient to Induce Apoptosis and Inhibit Cell Migration in Colon Cancer Cells

¹ Herbert Irving Comprehensive Cancer Center, ² Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, and ³ OSI Pharmaceuticals, Inc., Farmingdale, New York

The activation of protein kinase G (PKG) by cGMP has become of considerable interest as a novel molecular mechanism for the induction of apoptosis in cancer cells, because sulindac sulfone (exisulind, Aptosyn) and certain derivatives that inhibit cGMP-phosphodiesterases and thereby increase cellular levels of cGMP appear to induce apoptosis via this mechanism. However, other effects of these compounds have not been excluded, and the precise mechanism by which PKG activation induces apoptosis has not been elucidated in detail. To directly examine the effects of PKG on cell growth and apoptosis, we generated a series of mutants of PKG I: PKG IS65D, a constitutively activated point mutant; PKG I, a constitutively activated N-terminal truncated mutant; and PKG IK390R, a dominant-negative point mutant. A similar series of mutants of PKG Iß were also constructed (Deguchi et al., Mol. Cancer Ther., 1: 803–809, 2002). The present study demonstrates that when transiently expressed in SW480 colon cancer, the constitutively activated mutants of PKG Iß, and to a lesser extent PKG I, inhibit colony formation and induce apoptosis. We were not able to obtain derivatives of SW480 cells that stably expressed these constitutively activated mutants, presumably because of toxicity. However, derivatives that stably overexpressed wild-type PKG Iß displayed growth inhibition, whereas derivatives that stably expressed the dominant-negative mutant (KR) of PKG Iß grew more rapidly and were more resistant to Aptosyn-induced growth inhibition than vector control cells. Stable overexpression of PKG Iß was associated with decreased cellular levels of ß-catenin and cyclin D1 and increased levels of p21^CIP1. Reporter assays indicated that activation of PKG Iß inhibits the transcriptional activity of the cyclin D1 promoter. We also found that transient expression of the constitutively activated mutants of PKG Iß inhibited cell migration. Taken together, these results indicate that activation of PKG Iß is sufficient to inhibit growth and cell migration and induce apoptosis in human colon cancer cells and that these effects are associated with inhibition of the transcription of cyclin D1 and an increase in the expression of p21^CIP1.

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