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

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.

• Authors: Maria Chiara Proto, Donatella Fiore, Chiara Piscopo, Silvia Franceschelli, Valentina Bizzarro, Chiara Laezza, Gianluigi Lauro, Alessandra Feoli, Alessandra Tosco, Giuseppe Bifulco, Gianluca Sbardella, Maurizio Bifulco, Patrizia Gazzerro
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 11678 (09 15 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28916833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cannabinoid Receptor Antagonists
• Histone Acetyltransferases
• Rimonabant

Topics

• Animals
• Cannabinoid Receptor Antagonists (administration & dosage, pharmacology)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy)
• Colorectal Neoplasms (drug therapy, pathology)
• Disease Models, Animal
• Female
• Heterografts
• Histone Acetyltransferases (antagonists & inhibitors)
• Humans
• Mice, SCID
• Models, Biological
• Neoplasm Transplantation
• Rimonabant (administration & dosage, pharmacology)
• Treatment Outcome
• Wnt Signaling Pathway (drug effects)