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.
Footnotes
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This work was supported by the National Institutes of Health Grant 1R21 CA102616 (to S.C.G.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.117721.
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ABBREVIATIONS: CaP, carcinoma of prostate; C21H20O6, curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1–6-heptadine-3,5-dione; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TNF, tumor necrosis factor; NF, nuclear factor; IKK, IκB kinase; siRNA, small inhibitory RNA; MTS, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; p-Akt, phospho-Akt; PTEN, phosphatase and tensin homolog deleted on chromosome 10; XIAP, X-chromosome-linked inhibitor of apoptosis protein.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received November 28, 2006.
- Accepted February 7, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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