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-kappaB via inhibition of the prosurvival Akt signaling pathway

J Pharmacol Exp Ther. 2007 May;321(2):616-25. doi: 10.1124/jpet.106.117721. Epub 2007 Feb 8.


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)-kappaB. In the present study, we demonstrate that activated (phosphorylated) Akt kinase plays a pivotal role in regulation of NF-kappaB 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-kappaB is a downstream target of Akt, we investigated whether inhibition of NF-kappaB 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-kappaB. Furthermore, overexpression of constitutively active Akt1 in cancer cells prevented the inhibition of NF-kappaB 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-kappaB 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-kappaB, both curcumin and SH-6 decreased the levels of these proteins in PC3 cells through inhibition of NF-kappaB. 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-kappaB and NF-kappaB-dependent antiapoptotic Bcl-2, Bcl-xL, and XIAP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Curcumin / pharmacology*
  • Humans
  • I-kappa B Proteins / metabolism
  • Male
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / physiology
  • Phosphatidylinositols / pharmacology
  • Phosphorylation
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • RNA, Small Interfering / pharmacology
  • Signal Transduction / drug effects*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*


  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Phosphatidylinositols
  • RNA, Small Interfering
  • SH-6 compound
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • NF-KappaB Inhibitor alpha
  • Proto-Oncogene Proteins c-akt
  • Curcumin