Prostaglandin E(2) Reverses Curcumin-Induced Inhibition of Survival Signal Pathways in Human Colorectal Carcinoma (HCT-15) Cell Lines

Prostaglandin E(2) (PGE(2)) promotes tumor-persistent inflammation, frequently resulting in cancer. Curcumin is a diphenolic turmeric that inhibits carcinogenesis and induces apoptosis. PGE(2) inhibits curcumin-induced apoptosis; however, the underlying inhibitory mechanisms in colon cancer cells remain unknown. The aim of the present study is to investigate the survival role of PGE(2) and whether addition of exogenous PGE(2) affects curcumin-induced cell death. HCT-15 cells were treated with curcumin and PGE(2), and protein expression levels were investigated via Western blot. Reactive oxygen species (ROS) generation, lipid peroxidation, and intracellular glutathione (GSH) levels were confirmed using specific dyes. The nuclear factor-kappa B (NF-κB) DNA-binding was measured by electrophoretic mobility shift assay (EMSA). PGE(2) inhibited curcumin-induced apoptosis by suppressing oxidative stress and degradation of PARP and lamin B. However, exposure of cells to the EP2 receptor antagonist, AH6809, and the PKA inhibitor, H89, before treatment with PGE(2) or curcumin abolished the protective effect of PGE(2) and enhanced curcumin-induced cell death. PGE(2) activates PKA, which is required for cAMP-mediated transcriptional activation of CREB. PGE(2) also activated the Ras/Raf/Erk pathway, and pretreatment with PD98059 abolished the protective effect of PGE(2). Furthermore, curcumin treatment greatly reduced phosphorylation of CREB, followed by a concomitant reduction of NF-κB (p50 and p65) subunit activation. PGE(2) markedly activated nuclear translocation of NF-κB. EMSA confirmed the DNA-binding activities of NF-κB subunits. These results suggest that inhibition of curcumin-induced apoptosis by PGE(2) through activation of PKA, Ras, and NF-κB signaling pathways may provide a molecular basis for the reversal of curcumin-induced colon carcinoma cell death.