Inhibition of Wnt/β-Catenin pathway and Histone acetyltransferase activity by Rimonabant: a therapeutic target for colon cancer.

摘要: In a high percentage (≥85%) of both sporadic and familial adenomatous polyposis forms colorectal cancer (CRC), the inactivation APC tumor suppressor gene initiates formation modulates Wnt/β-Catenin transduction pathways involved in control cell proliferation, adhesion metastasis. Increasing evidence showed that endocannabinoids growth progression, vitro vivo. We evaluated effect Rimonabant, Cannabinoid Receptor 1 (CB1) inverse agonist, on pathway HCT116 SW48 lines carrying genetic profile metastatic CRC poorly responsive to chemotherapies. these models, Rimonabant inhibited canonical increased β-Catenin phosphorylation; cells, but not SW48, compound also triggered non activation through induction Wnt5A CaMKII. The Rimonabant-induced downregulation target genes was partially ascribable direct inhibition p300/KAT3B histone acetyltransferase, coactivator dependent regulation. Finally, xenografts, significantly reduced destabilized nuclear localization β-Catenin. Obtained data heavily supported rationale for use cannabinoids combined therapies harbouring activating mutations