Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner
Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner
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DOI：
10.1002/ijc.29573
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发表时间：
2015-10-15
影响因子：
6.4
通讯作者：
Santoni, Giorgio
中科院分区：
文献类型：
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作者：
Nabissi, Massimo;Morelli, Maria Beatrice;Santoni, Giorgio
胶质瘤干细胞样细胞（GSC）对应于肿瘤细胞亚群，参与多形性胶质母细胞瘤（GBM）肿瘤的起始和获得性化学抗性。目前，药物诱导分化被认为是根除这种肿瘤驱动细胞群的有前途的方法。近年来，大麻素（cannabinoids，CBs）在促进胶质细胞分化和抑制胶质瘤形成方面的作用已被证实。在本文中，我们证明大麻二酚（CBD）通过激活瞬时受体电位香草素-2（TRPV 2）触发GSC分化，激活自噬过程并抑制GSC增殖和克隆形成能力。最重要的是，CBD和卡莫司汀（BCNU）组合通过诱导凋亡性细胞死亡来克服GSC对BCNU处理的高抗性。急性髓性白血病（Aml-1）转录因子在GBM增殖和分化中起关键作用，并且已知Aml-1控制几种伤害感受性受体的表达。因此，我们评估了GSC中及其分化过程中Aml-1剪接变体（Aml-1a、B和c）的表达水平。我们发现Aml-1a在GSC分化过程中上调，其下调恢复分化的GSC中的干细胞表型。由于证明CBD也诱导TRPV 2表达并且TRPV 2参与GSC分化，我们评估了Aml-1a是否与TRPV 2启动子直接相互作用。在此，我们发现Aml-la结合TRPV 2启动子，并且Aml-la表达以TRPV 2和PI 3 K/AKT依赖性方式被CBD处理上调。总之，这些结果支持CBD诱导TRPV 2依赖性自噬过程刺激Aml-1a依赖性GSC分化的新机制，消除GSC中的BCNU化学抗性。
Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor initiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differentiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differentiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Altogether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs.