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.
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.
Deeb
Dorrah
D
Department of Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Jiang
Hao
H
Gao
Xiaohua
X
Al-Holou
Shaza
S
Danyluk
Andrew L
AL
Dulchavsky
Scott A
SA
Gautam
Subhash C
SC
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D010716:Phosphatidylinositols / Q000494:pharmacology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010716:Phosphatidylinositols; D034741:RNA, Small Interfering; C516024:SH-6 compound; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000072000:NF-KappaB Inhibitor alpha; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin