title: Anandamide drives cell cycle progression through CB1 receptors in a rat model of synchronized liver regeneration.
abstract: The endocannabinoid system, through cannabinoid receptor signaling by endocannabinoids, is involved in a wide range of functions and physiopathological conditions. To date, very little is known concerning the role of the endocannabinoids in the control and regulation of cell proliferation. An anti-proliferative action of CB1 signaling blockade in neurogenesis and angiogenesis argues in favor of proliferation-promoting functions of endocannabinoids through CB1 receptors when pro-growth signals are present. Furthermore, liver regeneration, a useful in vivo model of synchronized cell proliferation, is characterized by a peak of anandamide that elicits through CB1 receptor, the expression of critical mitosis genes. The aim of this study was to focus on the timing of endocannabinoid signaling changes during the different phases of the cell cycle, exploiting the rat liver regeneration model following partial hepatectomy, the most useful to study synchronized cell cycle in vivo. Hepatic regeneration led to increased levels of anandamide and endocannabinoid-like molecules oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the G1 phase of the cell cycle, with a concomitant increase in CB1 mRNA levels, whose protein expression peaked later during the S phase. Blocking of CB1 receptor with a low dose of the selective antagonist/inverse agonist SR141716 (0.7 mg/kg/dose) affected cell cycle progression reducing the expression of PCNA, and through the inhibition of pERK and pSTAT3 pathways. These results support the notion that the signaling mediated by anandamide through CB1 receptor may be important for the entry and progression of cells into the cell cycle and hence for their proliferation under mitogenic signals.
authors: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors: Simona
authors: S
authors: Pisanti
authors: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors: Paola
authors: P
authors: Picardi
authors: Department of Science, Section Biomedical Science and Technologies, University Roma Tre, Rome, Italy.
authors: Valentina
authors: V
authors: Pallottini
authors: Department of Science, Section Biomedical Science and Technologies, University Roma Tre, Rome, Italy.
authors: Chiara
authors: C
authors: Martini
authors: Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.
authors: Stefania
authors: S
authors: Petrosino
authors: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors: Maria Chiara
authors: MC
authors: Proto
authors: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors: Mario
authors: M
authors: Vitale
authors: Institute of Experimental Oncology and Endocrinology, IEOS, CNR, Naples, Italy.
authors: Chiara
authors: C
authors: Laezza
authors: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors: Patrizia
authors: P
authors: Gazzerro
authors: Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.
authors: Vincenzo
authors: V
authors: Di Marzo
authors: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors: Maurizio
authors: M
authors: Bifulco
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D018809:Proliferating Cell Nuclear Antigen; D043884:Receptor, Cannabinoid, CB1; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C094503:glyceryl 2-arachidonate; D048049:Extracellular Signal-Regulated MAP Kinases; C078814:anandamide