Curcumin [1,7-Bis(4-hydroxy-3-methoxyphenyl)-1–6-heptadine-3,5-dione; C₂₁H₂₀O₆] Sensitizes Human Prostate Cancer Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand/Apo2L-Induced Apoptosis by Suppressing Nuclear Factor-κB via Inhibition of the Prosurvival Akt Signaling Pathway

Abstract

Our previous studies have shown that dietary pigment curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1–6-heptadine-3,5-dione; C₂₁H₂₀O₆] sensitizes human prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L)-induced apoptosis by inhibiting nuclear factor (NF)-κB. In the present study, we demonstrate that activated (phosphorylated) Akt kinase plays a pivotal role in regulation of NF-κB and sensitization of LNCaP and PC3 prostate cancer cells to TRAIL by curcumin. Curcumin inhibited the expression of phospho-Akt (p-Akt), which was not due to activation of phosphatase and tensin homolog deleted on chromosome 10 phosphatase activity by curcumin. Because NF-κB is a downstream target of Akt, we investigated whether inhibition of NF-κB by curcumin is mediated through suppression of p-Akt. Data demonstrate that treatment of PC3 cells with SH-6 (JAm Chem Soc125:1144–1145, 2003), a specific inhibitor of Akt, or transfection with small inhibitory RNA (siRNA)-Akt not only inhibited p-Akt but also abrogated the expression and transcriptional activity of NF-κB. Furthermore, overexpression of constitutively active Akt1 in cancer cells prevented the inhibition of NF-κB by curcumin. In addition, treatment with SH-6 or transfection with siRNA-Akt sensitized PC3 cells to TRAIL-induced cytotoxicity. On the other hand, SH-6 does not inhibit NF-κB or sensitize DU145 cancer cells to TRAIL because these cells do not express p-Akt. Because expression of antiapoptotic Bcl-2, Bcl-xL, and X-chromosome-linked inhibitor of apoptosis protein (XIAP) is regulated by NF-κB, both curcumin and SH-6 decreased the levels of these proteins in PC3 cells through inhibition of NF-κB. Furthermore, gene silencing of Bcl-2 with siRNA-Bcl-2 sensitized PC3 cells to TRAIL. Collectively, these data define a pathway whereby curcumin sensitizes prostate cancer cells to TRAIL by inhibiting Akt-regulated NF-κB and NF-κB-dependent antiapoptotic Bcl-2, Bcl-xL, and XIAP.