Title:Targeting Proteasomal Pathways by Dietary Curcumin for Cancer Prevention and Treatment
Volume: 21
Issue: 14
Author(s): Noor Hasima and Bharat B. Aggarwal
Affiliation:
Keywords:
Cancer, cell death, curcumin, degradation, inflammatory protein, prevention, proteasome, transcription factor,
treatment, ubiquitination.
Abstract: Curcumin, a major component of the golden spice turmeric (Curcuma longa), has been linked with the prevention
and treatment of a wide variety of cancers through modulation of multiple cell signaling pathways. Since the first report
from our laboratory in 1995 that curcumin can inhibit activation of the proinflammatory transcription factor NF-κB
by inhibiting the 26S proteasomal degradation of IκBα, an inhibitor of NF-κB, this yellow pigment has been shown to inhibit
the protease activities of the proteasome. The carbonyl carbons of the curcumin molecule directly interact with the
hydroxyl group of the amino-terminal threonine residue of the proteasomal CT-L subunit of 20S proteasome and cellular
26S proteasome. Curcumin is also a potent inhibitor of COP9 signalosome and associated kinases, casein kinase 2 and
protein kinase D, all linked to the ubiquitin-proteasomal system (UPS). Curcumin can also directly inhibit ubiquitin
isopeptidases, a family of deubiquitinases (DUBs) that salvage ubiquitin for reuse by the 26S proteasome system. The inhibition
of this enzyme by curcumin is mediated through α,β-unsaturated ketone and two sterically accessible β-carbons.
Regulation of the UPS pathway by curcumin has been linked to regulation of cancer-linked inflammatory proteins (such
as COX-2 and iNOS), transcription factors (NF-κB, STAT3, Sp, AP-1, GADD153/CHOP, HIF-1α), growth factors
(VEGF, HER2), apoptotic proteins (p53, Bcl-2, survivin, DNA topoisomerase II, HDAC2, p300, hTERT) and cell cycle
proteins (cyclin D1, cyclin E, cyclin B, p21, p27) associated with the prevention and therapy of cancer. Interestingly, the
effect of curcumin on 26S proteasome appears to be dose-dependent, as low doses (≥1 µM) increase proteasome activity
whereas high doses (≤10 µM) inhibit the proteasome activity. In this review, we discuss in detail how modulation of these
targets by curcumin is linked to prevention and treatment of cancer.
