Abstract 4564: Elucidating the mechanism of the STAT3/NF-κB/EP4 signaling axis in pancreatic cancer

Despite recent advances to pancreatic cancer (PanCA) management, the 5 year survival rate remains only 7%. This poor survival rate highlights the importance of increasing our molecular understanding of PanCA pathogenesis to develop effective therapies to improve patient outcomes. We previously demonstrated that targeting the STAT3/NF-κB signaling axis with Nexrutine® (a Phellodendron amurense bark extract) was able to inhibit autophagy, ROS production, and proliferation in multiple PanCA cell lines. Our data also indicated the potential involvement of prostaglandin receptor EP4 in mediating these effects. To our surprise, we observed decreased levels of EP4 in human pancreatic tumors implicating a possible protective role. However, the mechanism behind STAT3/NF-κB signaling and its link to EP4 are still unknown. Using genetic and chemical inhibition of STAT3 and EP4, we have sought to define the STAT3/NF-κB/EP4 signaling axis. Our results indicate that inhibition of STAT3 via knockdown (STAT3 KD) using shRNA does not affect the proliferative ability or viability of PanCA cell lines when compared to non-transfected control (NTC) cells. Even though proliferation and viability were un-affected, STAT3 KD increased Cox-2 levels in a KRAS mutant cell line (Capan-2) and inhibited Cox-2 in a KRAS WT cell line (BxPC-3). Inhibition of EP4 increased STAT3 and NF-κB activity in KRAS mutant cell lines while decreasing activity in the KRAS WT cell line. Furthermore, EP4 inhibition increased protein levels of IL-6 and dual inhibition of STAT3 and EP4 yielded increased NF-κB activity and decreased Cox-2 levels. Converse experiments in cells treated with IL-6 revealed inhibited EP4 expression and decreased NF-κB activity. This may be the reason behind the increased STAT3 activity noted in EP4 inhibited KRAS mutant cells and supports the notion that EP4 may be protective against PanCA development. Taken together, these data suggests a feedback loop in regulating the STAT3/NF-κB/EP4 signaling cascade and that STAT3/NF-κB signaling axis members are differentially regulated upon STAT3 or EP4 inhibition possibly depending on KRAS status. Supported by Initiative for Maximizing Student Development (IMSD) Training Grant (R25 GM095480; NMJB), NCCIH (R01 AT007448; APK), and VA-MERIT Award (I01 BX 000766; APK) Citation Format: Amanda R. Munoz, James W. Freeman, Addanki P. Kumar. Elucidating the mechanism of the STAT3/NF-κB/EP4 signaling axis in pancreatic cancer. [abstract]. In: Proc