Targeting Proteasomal Pathways by Dietary Curcumin for Cancer Prevention and Treatment

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.

Effect of Curcumin on SMCT-1 Expression and Dichloroacetate Toxicity in HCT116 Colon Cancer Cells

“…This was not an unexpected result since curcumin has been shown to regulate proliferation of other cell types, including neural cells, 44 Schwann cells, 45 astrocytes, 46 whereas high concentrations are often toxic to various cancer cells and cell lines. [47][48][49] This protective effect of Cur was probably due to anti-oxidative effect 50 and transient activation of ERK and p38 kinase pathways at low concentrations. 51 However, higher concentration of Cur exhibits antiproliferative effect by controlling many signaling molecules such as p53, NF-κB, Akt, MAPK.…”

Modulation of the Proteasome Pathway by Nano-Curcumin and Curcumin in Retinal Pigment Epithelial Cells

“…Modulation of this pathway remains, however, an unexplored therapeutic target in retinal degenerative diseases. Curcumin has been reported to affect proteasome activity and expression in a biphasic, dosedependent manner [31]. Low concentrations of curcumin were found to up-regulate proteasome activity but high concentrations inhibited proteasome activity [31].…”

“…Second, curcumin inhibits COP9 signalosome (CSN) kinase activity [28,29]. CSN is a protein complex that controls the stability of many proteins such as ligases [30], and it possesses structural similarities to multiple non-ATPase subunits of the 19S lid of the proteasome [31]. The ligases interact with specific ubiquitinconjugating enzymes in the ubiquitination of substrates, and, as such, CSN functions as an interface between signal transduction and ubiquitin-dependent proteolysis [32].…”

“…Third, curcumin has been shown to inhibit ubiquitin isopeptidases, a family of cysteine proteases (deubiquitinases) responsible for the reutilization of ubiquitin by the 26S proteasome [27,33,34]. Curcumin contains an α,β-unsaturated ketone and 2 sterically accessible β-carbons that mediate inhibition of these enzymes [31].…”

Molecular aspects of breast cancer resistance to drugs (Review)

“…Another substance is the curcumin mayor component of the spice turmeric (Curcuma longa) and for several decades has proven to be a powerful anti-inflammatory agent and to have a great therapeutic potential against several types of cancer, blocking the transformation, proliferation and invasion of tumor cells (57)(58)(59). Curcumin suppresses multiple signaling pathways (58), such as caspase activation, induction of cell death receptors, aggregation of Fas receptors, induction of p53, and p21 pathways (57), release of apoptosis-inducing factor (57,60), regulation of the cell cycle (58,61), inhibition of PI3K-AKT activation, mTOR inhibition, downregulation of androgen receptors (57), inhibition of AMP-activated protein kinase, inhibition of COX2 and LOX 5, inhibition of STAT3 activation (57), c-Jun kinase activation, induction of DNA fragmentation, depletion of intracellular Ca 2 , mitochondrial activation, direct damage to the DNA, anti-apoptotic protein suppression, autophagy, antioxidant mechanisms, proteasome activation, NF-κβ inhibition, among others (58,61).…”