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.