Abstract
In a high percentage (≥85%) of both sporadic and familial adenomatous polyposis forms of colorectal cancer (CRC), the inactivation of the APC tumor suppressor gene initiates tumor formation and modulates the Wnt/β-Catenin transduction pathways involved in the control of cell proliferation, adhesion and metastasis. Increasing evidence showed that the endocannabinoids control tumor growth and progression, both in vitro and in vivo. We evaluated the effect of Rimonabant, a Cannabinoid Receptor 1 (CB1) inverse agonist, on the Wnt/β-Catenin pathway in HCT116 and SW48 cell lines carrying the genetic profile of metastatic CRC poorly responsive to chemotherapies. In these models, Rimonabant inhibited the Wnt/β-Catenin canonical pathway and increased β-Catenin phosphorylation; in HCT116 cells, but not in SW48, the compound also triggered the Wnt/β-Catenin non canonical pathway activation through induction of Wnt5A and activation of CaMKII. The Rimonabant-induced downregulation of Wnt/β-Catenin target genes was partially ascribable to a direct inhibition of p300/KAT3B histone acetyltransferase, a coactivator of β-Catenin dependent gene regulation. Finally, in HCT116 xenografts, Rimonabant significantly reduced tumor growth and destabilized the nuclear localization of β-Catenin. Obtained data heavily supported the rationale for the use of cannabinoids in combined therapies for metastatic CRC harbouring activating mutations of β-Catenin.
Highlights
The majority of both sporadic and familial forms of adenomatous polyposis (FAP) in colorectal cancer (CRC) originates from inactivation of APC (Adenomatous Polyposis Coli) tumor suppressor gene
In both HCT116 and SW48 cell lines, the increase of Caspase 3- and PARP-cleaved protein levels starting from 24 hours (Fig. 1d and see Supplementary Fig. S1a) strongly suggested induction of apoptosis
This was confirmed by results from human apoptosis antibody array, performed in HCT116 cells, revealing an upregulation of Cytochrome C and of death receptors (TRAILR-1, -2 and -3) and downregulation of Bcl-2 and X-linked Inhibitor of Apoptosis Protein (XIAP)
Summary
The majority of both sporadic and familial forms of adenomatous polyposis (FAP) in colorectal cancer (CRC) originates from inactivation of APC (Adenomatous Polyposis Coli) tumor suppressor gene. Anandamide (AEA), a cannabinoid receptor 1 (CB1) agonist, inhibits cholangiocarcinoma growth through activation of the non-canonical Wnt pathway mediated by Wnt5A8 and, in human breast cancer cells, methyl-F-AEA reduces β-Catenin levels, inhibits the transcriptional activation of TCF responsive elements and decreases the expression of mesenchymal markers[9]. These data strongly suggest our hypothesis of a potential effect of cannabinoids on the Wnt/β-Catenin in CRC, but to date no data dissected these interactions. We dissected the role of Rimonabant in CRC analyzing, in vitro and in vivo, its effects on the Wnt/β-Catenin mediated signalling
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