title: Interaction of endocannabinoid system and steroid hormones in the control of colon cancer cell growth.
abstract: Increasing evidence suggest the role of the cannabinoid receptors (CBs) in the control of cell survival or death and signaling pathways involved in tumor progression. Cancer cell lines are characterized by a subtle modulation of CB levels which produces a modified responsiveness to specific ligands, but the molecular mechanisms underlying these events are poorly and partially understood. We previously provided evidence that the endocannabinoid (EC) anandamide (AEA) exerts anti-proliferative effect likely by modulation of the expression of genes involved in the cellular fate. In this study we focused on the role of the CB1 receptor, ECs, and steroids in the mechanisms involved in colorectal cancer (CRC) cell growth inhibition in vitro. We demonstrated that, in DLD1 and SW620 cells, 17β-estradiol induced a specific and strong up-regulation of the CB1 receptor by triggering activation of the CB1 promoting region, localized at the exon 1 of the CNR1 gene. Moreover, treatment of DLD1 and SW620 cells with Met-F-AEA, a stable AEA-analogous, or URB597, a selective inhibitor of FAAH, induced up-regulation of CB1 expression by co-localization of PPARγ and RXRα at the promoting region. Finally, increased availability of AEA, of both exogenous and endogenous sources, induced the expression of estrogen receptor-beta in both cell lines. Our results partially elucidated the role of EC system in the molecular mechanisms enrolled by steroids in the inhibition of colon cancer cell growth and strongly suggested that targeting the EC system could represent a promising tool to improve the efficacy of CRC treatments.
authors.affiliation: Department of Pharmaceutical Sciences, University of Salerno, Fisciano, SA, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Proto
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gazzerro
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.forename: Antonietta
authors.initials: A
authors.lastname: Santoro
authors.forename: Anna M
authors.initials: AM
authors.lastname: Malfitano
authors.forename: Simona
authors.initials: S
authors.lastname: Pisanti
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
mesh_terms: D001095:Arachidonic Acids; D001483:Base Sequence; D015153:Blotting, Western; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063388:Endocannabinoids; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D053284:Polyunsaturated Alkamides; D011401:Promoter Regions, Genetic; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D047629:Estrogen Receptor beta; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; C078814:anandamide