QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.106.117721v1 321/2/616    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deeb, D. Articles by Gautam, S. C. Search for Related Content PubMed PubMed Citation Articles by Deeb, D. Articles by Gautam, S. C.

CELLULAR AND MOLECULAR

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-B via Inhibition of the Prosurvival Akt Signaling Pathway

Department of Surgery (D.D., X.G., S.A-H., A.L.D., S.A.D., S.C.G.) and Department of Neurology (H.J.), Henry Ford Health System, Detroit, Michigan

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)-B. In the present study, we demonstrate that activated (phosphorylated) Akt kinase plays a pivotal role in regulation of NF-B 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-B is a downstream target of Akt, we investigated whether inhibition of NF-B by curcumin is mediated through suppression of p-Akt. Data demonstrate that treatment of PC3 cells with SH-6 (JAm Chem Soc 125:1144–1145, 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-B. Furthermore, overexpression of constitutively active Akt1 in cancer cells prevented the inhibition of NF-B 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-B 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-B, both curcumin and SH-6 decreased the levels of these proteins in PC3 cells through inhibition of NF-B. 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-B and NF-B-dependent antiapoptotic Bcl-2, Bcl-xL, and XIAP.

Address correspondence to: Dr. Subhash C. Gautam, Surgical Research 4D, One Ford Place, Detroit, MI 48202. E-mail: sgautam1{at}hfhs.org

This article has been cited by other articles:

				Y. Jiao, J. Wilkinson IV, X. Di, W. Wang, H. Hatcher, N. D. Kock, R. D'Agostino Jr, M. A. Knovich, F. M. Torti, and S. V. Torti Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator Blood, January 8, 2009; 113(2): 462 - 469. [Abstract] [Full Text] [PDF]

				S. Yu, G. Shen, T. O. Khor, J.-H. Kim, and A.-N. T. Kong Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism Mol. Cancer Ther., September 1, 2008; 7(9): 2609 - 2620. [Abstract] [Full Text] [PDF]