Irrera Natasha, D'Ascola Angela, Pallio Giovanni, Bitto Alessandra, Mannino Federica, Arcoraci Vincenzo, Rottura Michelangelo, Ieni Antonio, Minutoli Letteria, Metro Daniela, Vaccaro Mario, Altavilla Domenica, Squadrito Francesco
Department of Clinical and Experimental Medicine, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy.
Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi", University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy.
Cancers (Basel). 2020 Apr 23;12(4):1038. doi: 10.3390/cancers12041038.
Glioblastomas are aggressive cancers characterized by uncontrolled proliferation and inflammation. b-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that showed an important anti-inflammatory effect through the interaction of CB2 and peroxisome proliferator-activated receptor gamma (PPARg) receptors. BCP effects were investigated in an in vitro model of glioblastoma. U-373 and U87, derived from a human glioblastoma, and human glioma stem-like cells (GSCs) were treated with BCP at different doses and time-points. AM360, a specific CB2 antagonist, was added 2 h before BCP treatment. BCP showed a significant anti-proliferative effect, reducing cell viability, inhibiting cell cycle, and increasing apoptosis, as demonstrated by Tunel assay, caspase-3 and caspase -9 activation. In addition, the pro-apoptotic BAX expression was increased, whereas the anti-apoptotic Bcl-2 expression was reduced. Treatment with BCP decreased Beclin-1, LC3 and p62/SQSTM1 expression, indicating a possible switch of autophagy to apoptosis. BCP's anti-inflammatory effect was demonstrated by NF-κB reduction, PPARg activation and TNF-a decrease; BCP significantly reduced Jun N-Terminal Kinase (JNK) expression as a consequence of TNF-α inhibition. AM360 abrogated BCP effects, thus demonstrating the BCP mechanism of action through the CB2 receptor. These findings let us hypothesize that BCP may act as a tumor suppressor in glioblastoma, acting on CB2 receptor and modulating JNK.
胶质母细胞瘤是一种侵袭性癌症，其特征为不受控制的增殖和炎症。β-石竹烯（BCP）是一种大麻素受体2（CB2）激动剂，通过CB2与过氧化物酶体增殖物激活受体γ（PPARγ）受体的相互作用显示出重要的抗炎作用。在胶质母细胞瘤的体外模型中研究了BCP的作用。用人胶质母细胞瘤来源的U-373和U87以及人胶质瘤干细胞样细胞（GSCs）在不同剂量和时间点用BCP处理。在BCP处理前2小时加入特异性CB2拮抗剂AM360。如Tunel检测、caspase-3和caspase-9激活所示，BCP显示出显著的抗增殖作用，降低细胞活力、抑制细胞周期并增加细胞凋亡。此外，促凋亡的BAX表达增加，而抗凋亡的Bcl-2表达降低。BCP处理降低了Beclin-1、LC3和p62/SQSTM1的表达，表明自噬可能向凋亡转变。通过NF-κB减少、PPARγ激活和TNF-α降低证明了BCP的抗炎作用；由于TNF-α抑制，BCP显著降低了Jun N端激酶（JNK）的表达。AM360消除了BCP的作用，从而证明了BCP通过CB2受体的作用机制。这些发现使我们推测BCP可能作为胶质母细胞瘤的肿瘤抑制因子，作用于CB2受体并调节JNK。
