Role of Protein Kinase G Isoforms in apoptosis mediated by Sulindac Sulfide

초록

Although the role of sulindac sulfide in inhibiting growth of colorectal cancer has been established, the precise mechanism is still obscure. We studied the effect of sulindac sulfide in SW480 human colon cancer cells to determine the underlying molecular mechanism of colorectal cancer regression. To elucidate the role of PKG in transcription control we constructed a series of expression vectors of wild type, constitutively active and dominant negative mutants of PKG. The transcriptional regulators of cyclin D1, such as, c-fos, c-jun, SRE and TRE were studied by using the luciferase reporter assay. Our data suggest that sulindac sulfide decreases the enzymatic activity of subcellular cGMP-phosphodiesterase, thereby increasing intracellular levels of cGMP and PKG. Increased PKG downregulate the transcription of cyclin D1 when transiently transfected in SW480 cells. Constitutively active mutants of PKG showed marked transcriptional downregulation of c-fos in SW480 cells. We also found that the constitutively active mutants of PKG negatively regulate the activation of SRE and TRE, suggesting their involvement in the regulation of cyclin D1.