Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients' cells.
Cannabinoid receptor CB1 regulates STAT3 activity and its expression dictates the responsiveness to SR141716 treatment in human glioma patients' cells.
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DOI：
10.18632/oncotarget.3895
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发表时间：
2015-06-20
期刊：
影响因子：
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通讯作者：
Bifulco M
中科院分区：
文献类型：
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作者：
Ciaglia E;Torelli G;Pisanti S;Picardi P;D'Alessandro A;Laezza C;Malfitano AM;Fiore D;Pagano Zottola AC;Proto MC;Catapano G;Gazzerro P;Bifulco M
在本文中，我们表明，与正常人星形胶质细胞（NHA）相比，大多数人脑肿瘤样品和细胞系过度表达大麻素受体CB 1，而均匀表达低水平的CB 2。这一发现促使我们研究SR 141716治疗CB 1失活的治疗性开发，关于其对胶质瘤的直接和间接细胞介导的作用。使用U251 MG胶质瘤细胞和来自表达不同水平CB 1的胶质瘤患者的原代肿瘤细胞系进行的功能研究强调了SR 141716通过G1期停滞诱导细胞凋亡的功效，并通过涉及STAT 3抑制的机制阻断TGF-β1分泌。根据STAT 3在免疫逃逸中的多变量作用，有趣的是，SR 141716也导致云母/B在应答性恶性胶质瘤细胞表面上的功能性和选择性表达，但不在NHA上。这使得SR 141716处理的胶质瘤细胞通过NKG 2D限制性机制成为同种异体NK细胞介导识别的有效靶点，从而引发它们的NK细胞抗肿瘤反应性。这些结果表明，CB 1和STAT 3参与了神经胶质瘤复杂生物学中的新致癌网络，其在患者中的表达水平决定了CB 1拮抗剂SR 141716在多模式神经胶质瘤破坏中的疗效。CB 1参与调节与几种生理病理条件下的存活、增殖、侵袭和血管生成相关的细胞过程。我们揭示了以前未被认识到的CB 1介导的人类胶质瘤进展的调节的分子机制，并提供了CB 1-STAT 3轴作为新的靶点和特异性治疗获益的预测生物标志物的首次和原始证明。事实上，CB 1拮抗作用能够控制肿瘤细胞分裂，同时使神经胶质瘤免疫可见并使免疫系统参与对抗它，这可能代表了其他已建立的化疗药物的有希望的替代方案。由于胶质瘤生物学的不同方面已经分别针对非常有限的成功，我们推测，CB 1抑制剂，其中包含在同一分子的细胞毒性潜力和高活性，以提高主管免疫监视机制，在一定程度上，似乎是相关的水平CB 1免疫反应，可能有深远的影响，探索新的治疗抗胶质瘤的行动。
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.