title: Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients' cells.
abstract: Herein we show that a majority of human brain tumor samples and cell lines over-expressed cannabinoid receptor CB1 as compared to normal human astrocytes (NHA), while uniformly expressed low levels of CB2. This finding prompted us to investigate the therapeutic exploitation of CB1 inactivation by SR141716 treatment, with regard to its direct and indirect cell-mediated effects against gliomas. Functional studies, using U251MG glioma cells and primary tumor cell lines derived from glioma patients expressing different levels of CB1, highlighted SR141716 efficacy in inducing apoptosis via G1 phase stasis and block of TGF-β1 secretion through a mechanism that involves STAT3 inhibition. According to the multivariate role of STAT3 in the immune escape too, interestingly SR141716 lead also to the functional and selective expression of MICA/B on the surface of responsive malignant glioma cells, but not on NHA. This makes SR141716 treated-glioma cells potent targets for allogeneic NK cell-mediated recognition through a NKG2D restricted mechanism, thus priming them for NK cell antitumor reactivity. These results indicate that CB1 and STAT3 participate in a new oncogenic network in the complex biology of glioma and their expression levels in patients dictate the efficacy of the CB1 antagonist SR141716 in multimodal glioma destruction.
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ciaglia
authors.affiliation: "G.Rummo" Medical Hospital, Department of Neurosurgery, Benevento, Italy.|Neurosurgery Unit A.O. San Giovanni di Dio e Ruggi d' Aragona - Salerno's School of Medicine, Largo Città di Ippocrate, Salerno, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Torelli
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pisanti
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Picardi
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Institute of Endocrinology and Experimental Oncology, IEOS CNR, Naples, Italy.|Department of Biology and Cellular and Molecular Pathology, University of Naples Federico II, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Malfitano
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Fiore
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Antonio Christian
authors.initials: AC
authors.lastname: Pagano Zottola
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Proto
authors.affiliation: "G.Rummo" Medical Hospital, Department of Neurosurgery, Benevento, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Catapano
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gazzerro
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.|Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000077285:Rimonabant; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D010880:Piperidines; D011720:Pyrazoles; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053773:Transforming Growth Factor beta1; D000077285:Rimonabant
keywords: CB1; MICA; NK cells; STAT3; gliomas