Recent studies indicate that the induction of apoptosis in human colon cancer cells by certain non-steroidal anti-inflammatory drugs (NSAIDs) involves increased expression of 15-LOX-1 and synthesis of its major product 13-S-hydroxyoctadecadienoic acid (13-S-HODE). Evidence was obtained that this occurs via a cyclooxygenase-2 (COX-2)-independent mechanism, but the actual mechanism of induction of 15-LOX-1 by these compounds is not known (Shureiqi et al. Cancer Res. 60, 6846-6850, 2000). There is extensive evidence that treatment of SW480 human colon cancer cells with sulindac sulfone (Aptosyn) or the related derivative OSI 461, both of which lack COX-2 inhibitory activity, causes an increase in intracellular levels of cGMP, thus activating PKG, which then activates pathways that lead to apoptosis. Therefore, in the present study, we examined the effects of various agents that cause increased cellular levels of cGMP on the expression of 15-LOX-1 in SW480 human colon cancer cells. Treatment of the cells with Aptosyn, sulindac sulfide, OSI 461, the guanylyl cyclase activator YC-1, or the cell-permeable cGMP compound 8-pCPT-cGMP caused an increase in cellular levels of 15-LOX-1 within 24 hours. Aptosyn also increased cellular levels of 15-LOX-1 mRNA suggesting that the effect was at the level of transcription. Treatment of SW480 cells with the PKG inhibitor Rp-8-pCPT-cGMP blocked Aptosyn-induced 15-LOX-1 expression. Furthermore, derivatives of SW480 cells that were engineered to stably overexpress wild type PKG Iβ displayed increased cellular levels of 15-LOX-1 when compared to vector control cells. This may explain, at least in part, the slower growth rate of these cells. Taken together, these results provide evidence that the cGMP/PKG pathway plays an important role in the induction of 15-LOX-1 expression by NSAIDs and related agents. Our findings also provide further insights into the mechanisms by which activation of PKG can lead to the induction of apoptosis in colon cancer cells.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]