Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo.
Curcumin (diferuloylmethane) is the major active ingredient of turmeric (Curcuma longa) used in South Asian cuisine for centuries. Curcumin has been shown to inhibit the growth of transformed cells and to have a number of potential molecular targets. However, the essential molecular targets of curcumin under physiologic conditions have not been completely defined. Herein, we report that the tumor cellular proteasome is most likely an important target of curcumin. Nucleophilic susceptibility and in silico docking studies show that both carbonyl carbons of the curcumin molecule are highly susceptible to a nucleophilic attack by the hydroxyl group of the NH(2)-terminal threonine of the proteasomal chymotrypsin-like (CT-like) subunit. Consistently, curcumin potently inhibits the CT-like activity of a purified rabbit 20S proteasome (IC(50) = 1.85 micromol/L) and cellular 26S proteasome. Furthermore, inhibition of proteasome activity by curcumin in human colon cancer HCT-116 and SW480 cell lines leads to accumulation of ubiquitinated proteins and several proteasome target proteins, and subsequent induction of apoptosis. Furthermore, treatment of HCT-116 colon tumor-bearing ICR SCID mice with curcumin resulted in decreased tumor growth, associated with proteasome inhibition, proliferation suppression, and apoptosis induction in tumor tissues. Our study shows that proteasome inhibition could be one of the mechanisms for the chemopreventive and/or therapeutic roles of curcumin in human colon cancer. Based on its ability to inhibit the proteasome and induce apoptosis in both HCT-116 and metastatic SW480 colon cancer cell lines, our study suggests that curcumin could potentially be used for treatment of both early-stage and late-stage/refractory colon cancer.
Milacic
Vesna
V
Barbara Ann Karmanos Cancer Institute, Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Banerjee
Sanjeev
S
Landis-Piwowar
Kristin R
KR
Sarkar
Fazlul H
FH
Majumdar
Adhip P N
AP
Dou
Q Ping
QP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D023041:Xenograft Model Antitumor Assays
D007976:Leupeptins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053179:Caspase 7; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D003474:Curcumin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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