Soliman Eman, Van Dross Rukiyah
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
Mol Carcinog. 2016 Nov;55(11):1807-1821. doi: 10.1002/mc.22429. Epub 2015 Oct 29.
Endocannabinoids are neuromodulatory lipids that regulate central and peripheral physiological functions. Endocannabinoids have emerged as effective antitumor drugs due to their ability to induce apoptosis in various cancer studies. The G-protein coupled cannabinoid receptors (CB1 and CB2) and the TRPV1 ion channel were reported to mediate the antiproliferative activity of endocannabinoids. However, receptor-independent effects also account for their activity. Our previous studies showed that the antiproliferative activity of anandamide (AEA) was regulated by cyclooxygenase-2 (COX-2) via induction of endoplasmic reticulum (ER) stress. We also determined that AEA induced oxidative stress. However, the role of oxidative stress, the cannabinoid receptors, and TRPV1 in AEA-induced ER stress-apoptosis was unclear. Therefore, the current study examines the role of oxidative stress in ER stress-apoptosis and investigates whether this effect is modulated by CB1, CB2, or TRPV1. In non-melanoma skin cancer (NMSC) cells, AEA reduced the total intracellular level of glutathione and induced oxidative stress. To evaluate the importance of oxidative stress in AEA-induced cell death, the antioxidants, N-acetylcysteine (NAC) and Trolox, were utilized. Each antioxidant ameliorated the antiproliferative effect of AEA. Furthermore, Trolox inhibited AEA-induced CHOP10 expression and caspase 3 activity, indicating that oxidative stress was required for AEA-induced ER stress-apoptosis. On the other hand, selective blockade of CB1, CB2, and TRPV1 did not inhibit AEA-induced oxidative stress or ER stress-apoptosis. These findings suggest that AEA-induced ER stress-apoptosis in NMSC cells is mediated by oxidative stress through a receptor-independent mechanism. Hence, receptor-independent AEA signaling pathways may be targeted to eliminate NMSC. © 2015 Wiley Periodicals, Inc.
内源性大麻素是调节中枢和外周生理功能的神经调节脂质。由于内源性大麻素在各种癌症研究中具有诱导细胞凋亡的能力，它们已成为有效的抗肿瘤药物。据报道，G蛋白偶联大麻素受体（CB1和CB2）以及TRPV1离子通道介导内源性大麻素的抗增殖活性。然而，非受体依赖性效应也解释了它们的活性。我们之前的研究表明，花生四烯乙醇胺（AEA）的抗增殖活性通过诱导内质网（ER）应激由环氧合酶-2（COX-2）调节。我们还确定AEA诱导氧化应激。然而，氧化应激、大麻素受体和TRPV1在AEA诱导的ER应激-细胞凋亡中的作用尚不清楚。因此，本研究探讨氧化应激在ER应激-细胞凋亡中的作用，并研究这种效应是否受CB1、CB2或TRPV1调节。在非黑色素瘤皮肤癌（NMSC）细胞中，AEA降低了细胞内谷胱甘肽的总水平并诱导氧化应激。为了评估氧化应激在AEA诱导的细胞死亡中的重要性，使用了抗氧化剂N-乙酰半胱氨酸（NAC）和生育三烯酚。每种抗氧化剂都改善了AEA的抗增殖作用。此外，生育三烯酚抑制了AEA诱导的CHOP10表达和半胱天冬酶3活性，表明氧化应激是AEA诱导的ER应激-细胞凋亡所必需的。另一方面，选择性阻断CB1、CB2和TRPV1并未抑制AEA诱导的氧化应激或ER应激-细胞凋亡。这些发现表明，AEA在NMSC细胞中诱导的ER应激-细胞凋亡是通过非受体依赖性机制由氧化应激介导的。因此，非受体依赖性AEA信号通路可能是消除NMSC的靶点。©2015威利期刊公司
