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.
Highlights
Glioblastoma multiforme (GBM) is a fatal disease characterized by uncontrolled cellular proliferation, diffuse infiltration, a tendency for necrosis, significant angiogenesis, intense resistance to apoptosis, and widespread genomic aberrations
The results showed that protein expression of CB1 receptor was up-regulated in all glioma cell lines tested compared with normal astrocytes
To gain better insight into the biological processes modulated by SR141716 treatment in glioma cells, U251 cell line was used as a model system for further studies, as this cell line is one of the most aggressive glioblastoma cell lines with a considerable expression of CB1
Summary
Glioblastoma multiforme (GBM) is a fatal disease characterized by uncontrolled cellular proliferation, diffuse infiltration, a tendency for necrosis, significant angiogenesis, intense resistance to apoptosis, and widespread genomic aberrations. The ubiquitous regulatory action of the endocannabinoid system in health and disease emphasizes the role of this endogenous system in several physiopathological processes and makes its pharmacological manipulation a promising strategy for the management of many different diseases, including cancer. This system, composed of cannabinoid receptors CB1 and CB2, their endogenous ligands (endocannabinoids, eg, anandamide) and the enzymes for their metabolism, has been shown to be involved in the control of proliferation, migration, and invasive behavior of a wide variety of tumor types [2]. Little is currently known about the biological role of the endocannabinoid system in cancer physiopathology and many basic questions remain unanswered
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