Kim Hyun Hee, Lee Suk-Young, Lee Dae-Hee
Department of Marine Bio Food Science, Gangneung-Wonju National University, Jukheon-gil 7, Gangneung 25457, Republic of Korea.
Department of Pathology, Korea University Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea.
Cancers (Basel). 2024 Sep 5;16(17):3092. doi: 10.3390/cancers16173092.
Pancreatic cancer is a refractory cancer with limited treatment options. Various cancer types are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Eugenol, the main component of clove oil, exhibits anticancer, anti-inflammatory, and antioxidant effects. However, no studies have reported that eugenol increases TRAIL sensitivity by upregulating death receptor (DR) expression. Here, we aimed to investigate eugenol as a potent TRAIL sensitizer. Increased apoptosis and inhibition of cell proliferation was observed in pancreatic cancer cells treated with eugenol and TRAIL compared with those treated with eugenol alone. Eugenol upregulated the expression of DR5, inhibited the FLICE-inhibitory protein (FLIP), an anti-apoptotic protein, and increased p53, a tumor suppressor protein. In addition, eugenol induced the generation of reactive oxygen species (ROS) and caused endoplasmic reticulum (ER) stress. C/EBP-homologous protein (CHOP) knockdown using siRNA decreased the expression of DR5 and reduced the combined effects of eugenol and TRAIL. These results demonstrate that eugenol enhances TRAIL-induced apoptosis by upregulating DR5 through the ROS-mediated ER stress-CHOP pathway, which enhances ER stress by inducing p53 and downregulating FLIP expression. This suggests that eugenol has the potential to treat pancreatic cancer by increasing cell sensitivity to TRAIL.
胰腺癌是一种治疗选择有限的难治性癌症。多种癌症类型对肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有抗性。丁香酚是丁香油的主要成分，具有抗癌、抗炎和抗氧化作用。然而，尚无研究报道丁香酚通过上调死亡受体（DR）表达来增加TRAIL敏感性。在此，我们旨在研究丁香酚作为一种有效的TRAIL增敏剂。与单独用丁香酚处理的胰腺癌细胞相比，用丁香酚和TRAIL处理的细胞凋亡增加且细胞增殖受到抑制。丁香酚上调DR5的表达，抑制抗凋亡蛋白FLICE抑制蛋白（FLIP），并增加肿瘤抑制蛋白p53。此外，丁香酚诱导活性氧（ROS）生成并引起内质网（ER）应激。使用小干扰RNA敲低C/EBP同源蛋白（CHOP）可降低DR5的表达，并降低丁香酚和TRAIL的联合作用。这些结果表明，丁香酚通过ROS介导的ER应激-CHOP途径上调DR5，从而增强TRAIL诱导的细胞凋亡，该途径通过诱导p53和下调FLIP表达来增强ER应激。这表明丁香酚有可能通过增加细胞对TRAIL的敏感性来治疗胰腺癌。
