Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients’ cells
Metrics: PDF 1993 views | HTML 3399 views | ?
Elena Ciaglia1,2, Giovanni Torelli3,4, Simona Pisanti1,2, Paola Picardi1,2, Alba D’Alessandro2, Chiara Laezza5,6, Anna Maria Malfitano1,2, Donatella Fiore2, Antonio Christian Pagano Zottola2, Maria Chiara Proto2, Giuseppe Catapano3, Patrizia Gazzerro2, Maurizio Bifulco1,2
1Department of Medicine and Surgery, University of Salerno, Baronissi Salerno, Italy
2Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
3”G.Rummo” Medical Hospital, Department of Neurosurgery, Benevento, Italy
4Neurosurgery Unit A.O. San Giovanni di Dio e Ruggi d’ Aragona - Salerno’s School of Medicine, Largo Città di Ippocrate, Salerno, Italy
5Institute of Endocrinology and Experimental Oncology, IEOS CNR, Naples, Italy
6Department of Biology and Cellular and Molecular Pathology, University of Naples Federico II, Naples, Italy
Maurizio Bifulco, e-mail: [email protected]
Elena Ciaglia, e-mail: [email protected]
Keywords: STAT3, CB1, MICA, NK cells, gliomas
Received: February 18, 2015 Accepted: April 29, 2015 Published: May 11, 2015
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.
CB1 is implicated in the regulation of cellular processes linked to survival, proliferation, invasion and angiogenesis in several physio-pathological conditions. We shed light on previously unrecognized molecular mechanism of CB1-mediated modulation of human glioma progression and provide the first and original demonstration of CB1-STAT3 axis as a new target and predictor biomarkers of the benefit from specific therapies. Indeed CB1 antagonism capable of tumoral cell division’ control while making the glioma immunovisible and engaging the immune system to fight it may represent a hopeful alternative to other established chemotherapeutics. Because different aspects of glioma biology have been separately targeted with very limited success, we speculate that CB1 inhibitors which enclose in the same molecule cytotoxic potential and high activity to boost competent immune surveillance mechanisms, at a degree that seems to be correlated to the levels of CB1 immunoreactivity, might have profound implications for exploring new therapeutic anti-glioma actions.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.