title: Anti Proliferative and Pro Apoptotic Effects of Flavonoid Quercetin Are Mediated by CB1 Receptor in Human Colon Cancer Cell Lines.
abstract: Quercetin, the major constituent of flavonoid and widely present in fruits and vegetables, is an attractive compound for cancer prevention due to its beneficial anti proliferative effects, showing a crucial role in the regulation of apoptosis and cell cycle signaling. In vitro studies have demonstrated that quercetin specifically influences colon cancer cell proliferation. Our experiments, using human colon adenocarcinoma cells, confirmed the anti proliferative effect of quercetin and gave intriguing new insight in to the knowledge of the mechanisms involved. We observed a significant increase in the expression of the endocannabinoids receptor (CB1-R) after quercetin treatment. CB1-R can be considered an estrogen responsive receptor and quercetin, having a structure similar to that of the estrogens, can interact with CB1-R leading to the regulation of cell growth. In order to clarify the contribution of the CB1-R to the quercetin action, we investigated some of the principal molecular pathways that are inhibited or activated by this natural compound. In particular we detected the inhibition of the major survival signals like the PI3K/Akt/mTOR and an induction of the pro apoptotic JNK/JUN pathways. Interestingly, the metabolism of β-catenin was modified by flavonoid both directly and through activated CB1-R. In all the experiments done, the quercetin action has proven to be reinforced by anandamide (Met-F-AEA), a CB1-R agonist, and partially counteracted by SR141716, a CB1-R antagonist. These findings open new perspectives for anticancer therapeutic strategies.
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases S. de Bellis, Bari, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Refolo
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases S. de Bellis, Bari, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: D'Alessandro
authors.affiliation: Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy.
authors.forename: Natascia
authors.initials: N
authors.lastname: Malerba
authors.affiliation: Institute of Endocrinology and Experimental Oncology-CNR, Napoli, Italy.|Department of Biology and Cellular Pathology, University Federico II, Napoli, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Institute for Digestive Diseases S. de Bellis, Bari, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Messa
authors.affiliation: Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Caruso
authors.affiliation: Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Notarnicola
authors.affiliation: Nutritional Biochemistry, National Institute for Digestive Diseases S. de Bellis, Bari, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tutino
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011794:Quercetin / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C571130:CNR1 protein, human; D063386:Cannabinoid Receptor Agonists; D043884:Receptor, Cannabinoid, CB1; D011794:Quercetin