Can Zhou, Lele Song, Zhirui Zhang, Qiong Pan, Yuzhong Chen, Lingling Liu, Surong Zhao, Yiming Sun, Pei Zhang, Chenchen Jiang, Liu Hao
aFaculty of Pharmacy, Bengbu Medical College bDepartment of Pharmacy cDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College dDepartment of Pharmacy, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, People's Republic of China eSchool of Medicine and Public Health, Faculty of Health, Newcastle University, Newcastle, New South Wales, Australia.
Anticancer Drugs. 2017 Aug;28(7):739-749. doi: 10.1097/CAD.0000000000000502.
Past reports have shown that the sensitivity of cancer cells to TRAIL-induced apoptosis is related to their expression of TRAIL-death receptors on the cell surface. However, the level of TRAIL-death receptors expression on cancer cells is always low. Our previous research showed that nasopharyngeal carcinoma (NPC) cells have a poor sensitivity to low doses of TRAIL. Here, we evaluated combined treatment with the energy inhibitor 3-bromopyruvate (3BP) and TRAIL as a method to produce an increased apoptotic response in NPC cells. The results showed that 3BP and TRAIL together produced higher cytotoxicity and increased TRAIL-R2 expression in NPC cells compared with the effects of either 3BP or TRAIL alone. These findings led us to hypothesize that 3BP may sensitize NPC cells to TRAIL. 3BP is a metabolic blocker that inhibits hexokinase II activity, suppresses ATP production, and induces endoplasmic reticulum (ER) stress. Our results showed that 3BP also activated AMP-activated protein kinase, which we found to play an important role in the induction of ER stress by 3BP. Furthermore, the induction of TRAIL-R2 expression and the sensitization of the NPC cells to TRAIL by 3BP were reduced when we inhibited the expression of CHOP. Taken together, our results showed that a low dose of 3BP sensitized NPC cells to TRAIL-induced apoptosis by the upregulation of CHOP, which was mediated by the activation of AMP-activated protein kinase and ER stress. The results showed that 3BP is a promising candidate agent for enhancing the therapeutic response to TRAIL in NPC.
以往的报道表明，癌细胞对TRAIL诱导的凋亡的敏感性与其在细胞表面的TRAIL死亡受体表达有关。然而，癌细胞上TRAIL死亡受体的表达水平一直很低。我们之前的研究表明，鼻咽癌（NPC）细胞对低剂量TRAIL的敏感性较差。在此，我们评估了能量抑制剂3-溴丙酮酸（3BP）与TRAIL联合治疗作为一种在NPC细胞中产生增强凋亡反应的方法。结果表明，与单独使用3BP或TRAIL的效果相比，3BP和TRAIL联合使用在NPC细胞中产生了更高的细胞毒性并增加了TRAIL-R2的表达。这些发现使我们推测3BP可能使NPC细胞对TRAIL敏感。3BP是一种代谢阻滞剂，可抑制己糖激酶II的活性，抑制ATP生成，并诱导内质网（ER）应激。我们的结果表明，3BP还激活了AMP激活的蛋白激酶，我们发现其在3BP诱导的ER应激中起重要作用。此外，当我们抑制CHOP的表达时，3BP诱导的TRAIL-R2表达增加以及NPC细胞对TRAIL的敏感性降低。综上所述，我们的结果表明，低剂量的3BP通过上调CHOP使NPC细胞对TRAIL诱导的凋亡敏感，这是由AMP激活的蛋白激酶和ER应激的激活介导的。结果表明，3BP是增强NPC对TRAIL治疗反应的有前景的候选药物。
