Cancer Therapy: Preclinical Combined Targeting of STAT3/NF-kB/COX-2/EP4 for Effective Management of Pancreatic Cancer

Purpose:Near equal rates of incidence and mortality emphasize the need for novel targeted approaches for better management of patients with pancreatic cancer. Inflammatory molecules NF-kB and STAT3 are overexpressed in pancreatic tumors. Inhibition of one protein allows cancer cells to survive using the other. The goal of this study is to determine whether targeting STAT3/NF-kB crosstalk with a natural product Nexrutine can inhibit inflammatory signaling in pancreatic cancer. ExperimentalDesign:HPNE,HPNE-Ras, BxPC3, Capan-2,MIAPaCa-2, andAsPC-1 cells were tested for growth, apoptosis, cyclooxygenase-2 (COX-2), NF-kB, and STAT3 level in response to Nexrutine treatment. Transient expression, gel shift, chromatin immunoprecipitation assay was used to examine transcriptional regulation of COX-2. STAT3 knockdownwas used to decipher STAT3/NF-kB crosstalk. Histopathologic and immunoblotting evaluation was performed on BK5–COX-2 transgenic mice treated with Nexrutine. In vivo expression of prostaglandin receptor E-prostanoid 4 (EP4) was analyzed in a retrospective cohort of pancreatic tumors using a tissue microarray. Results:Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of STAT3,NF-kB, and their crosstalk led to transcriptional suppression of COX-2 and subsequent decreased levels of prostaglandin E2 (PGE2) and PGF2. STAT3 knockdown studies suggest STAT3 as negative regulator ofNF-kB activation. Nexrutine intervention reduced the levels ofNF-kB, STAT3, and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors. Conclusions: Dual inhibition of STAT3–NF-kB by Nexrutine may overcome problems associated with inhibition of either pathway. Clin Cancer Res; 20(5); 1259–73. 2014 AACR.