Curcumin: a therapeutic strategy in cancers by inhibiting the canonical WNT/β-catenin pathway

Abstract

Numerous studies have presented that curcumin could have a positive effect in the prevention of cancer and then in tumor therapy. Several hypotheses have highlighted that curcumin could decreases tumor growth and invasion by acting on both chronic inflammation and oxidative stress. This review focuses on the interest of use curcumin in cancer therapy by acting on the WNT/β-catenin pathway to repress chronic inflammation and oxidative stress. In the cancer process, one of the major signaling pathways involved is the WNT/β-catenin pathway, which appears to be upregulated. Curcumin administration participates to the downregulation of the WNT/β-catenin pathway and thus, through this action, in tumor growth control. Curcumin act as PPARγ agonists. The WNT/β-catenin pathway and PPARγ act in an opposed manner. Chronic inflammation, oxidative stress and circadian clock disruption are common and co-substantial pathological processes accompanying and promoting cancers. Circadian clock disruption related to the upregulation of the WNT/β-catenin pathway is involved in cancers. By stimulating PPARγ expression, curcumin can control circadian clocks through the regulation of many key circadian genes. The administration of curcumin in cancer treatment would thus appear to be an interesting therapeutic strategy, which acts through their role in regulating WNT/β-catenin pathway and PPARγ activity levels.

Keywords: Cancer; Curcumin; Inflammation; Oxidative stress; PPARγ; WNT pathway.

Fig. 1

Relationship between ROS and chronic inflammation

Fig. 2

The canonical WNT/β-catenin pathway. WNT (−). Under resting condition, the cytoplasmic β-catenin is bound to its destruction complex, consisting of APC, AXIN and GSK-3β. After CK-1 phosphorylates on Ser45 residue, β-catenin is further phosphorylated on Thr41, Ser37, and Ser33 residues by GSK-3β. Then, phosphorylated β-catenin is degraded into the proteasome. Therefore, the cytosolic level of β-catenin is kept low in the absence of WNT ligands. If β-catenin is not present in the nucleus, the TCF/LEF complex cannot activate the target genes. DKK1 inhibits the WNT/β-catenin pathway by binding to WNT ligands or LRP5/6. WNT (+). When WNT ligands bind to both FZD and LRP5/6, DSH is recruited and phosphorylated by FZD. Phosphorylated DSH in turn recruits AXIN, which dissociates the β-catenin destruction complex. Therefore, β-catenin escapes from phosphorylation and subsequently accumulates in the cytosol. The accumulated cytosolic β-catenin goes into the nucleus, where it binds to TCF/LEF and activates the transcription of target genes

Fig. 3

Circadian clock genes. The clock consists of a stimulatory loop, with the Bmal1/Clock heterodimer stimulating the transcription of Per and Cry genes, and an inhibitory feedback loop with the Per/Cry heterodimer translocating to the nucleus and repressing the transcription of the Clock and Bmal1 genes. An additional loop involves the RORs and RevErbs factors with a positive feedback by ROR and a negative feedback by RevErbs

Fig. 4

Interactions between PPARγ, WNT pathway and circadian rhythms in cancer. Dysregulation of melatonin and nocturin decreases the expression of PPARγ in cancer. Decreased PPARγ dysregulates Bmal1/Clock heterodimer. Decreased PPARγ expression directly activates the formation of the heterodimer Bmal1/Clock and β-catenin cytosolic accumulation but inhibits the activity of GSK3, the main inhibitor of the WNT/β-catenin pathway. Bmal1/Clock knockout also decreases GSK3 activity and activates the WNT/β-catenin pathway and its downstream gene c-Myc through the activation of the heterodimer Per/Cry. The activation of the WNT/β-catenin pathway by the cytosolic accumulation of the β-catenin and the activation of c-Myc lead to cancer initiation (oxidative stress and chronic inflammation)

Fig. 5

Curcumin actions on the WNT pathway in cancer therapy. Curcumin modulates cancer progression through the regulation of several signaling pathways. Attachment of ligands to their corresponding receptors leads to the activation of downstream pathways, including PI3K, STAT, caspase. These signaling pathways have a major role in cell survival, proliferation, apoptosis, angiogenesis, migration and metastasis. The decrease of Akt pathway by curcumin leads to the activation of p53 signaling and Bad-mediated apoptotic pathway contributing to cancer cell survival. Moreover, the downregulation of Akt pathway is associated with the inhibition of NF-ϰB signaling pathway, responsible for the inflammation. By decreasing WNT pathway, curcumin leads to the activate GSK-3β activity which induces β-catenin phosphorylation and then its degradation. The inhibition of the WNT pathway is associated with the control of proliferation and angiogenesis. The increase of caspase pathway by curcumin leads to apoptosis whereas curcumin decreases the STAT3 signaling pathway to counteract migration and proliferation. The activation of PPARγ by curcumin leads to the downregulation of the WNT pathway and the control of inflammation. WNT pathway downregulation results in the decrease of PI3K and STAT3 signaling pathways but the increase of caspase

Fig. 6

Beneficial role of curcumin in cancer. (1) Curcumin reduces oxidative stress; (2) Curcumin reduces chronic inflammation; (3) Curcumin inhibits Akt pathway activity; (4) Curcumin downregulates WNT pathway and its target genes, inhibits Bcl-2 and activates GSK-3beta; (5) Curcumin inhibits NF-ϰB and COX-2