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KMID : 0578320140370120899
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Molecules and Cells
2014 Volume.37 No. 12 p.899 ~ p.906
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Prostaglandin E2 Reverses Curcumin-Induced Inhibition of Survival Signal Pathways in Human Colorectal Carcinoma (HCT-15) Cell Lines
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Shehzad Adeeb
Islam Salman Ul
Lee Jae-Tae
Lee Young-Sup
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Abstract
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Prostaglandin E2 (PGE2) promotes tumor-persistent inflammation, frequently resulting in cancer. Curcumin is a diphenolic turmeric that inhibits carcinogenesis and induces apoptosis. PGE2 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 PGE2 and whether addition of exogenous PGE2 affects curcumin-induced cell death. HCT-15 cells were treated with curcumin and PGE2, 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). PGE2 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 PGE2 or curcumin abolished the protective effect of PGE2 and enhanced curcumin-induced cell death. PGE2 activates PKA, which is required for cAMP-mediated transcriptional activation of CREB. PGE2 also activated the Ras/Raf/Erk pathway, and pretreatment with PD98059 abolished the protective effect of PGE2. Furthermore, curcumin treatment greatly reduced phosphorylation of CREB, followed by a concomitant reduction of NF-κB (p50 and p65) subunit activation. PGE2 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 PGE2 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.
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KEYWORD
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apoptosis, curcumin, prostaglandin E2, survival signal
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