Liang Yiyao, Wei Minyan, Yao Yunan, Chen Baizhong, Deng Jinji, Xu Shiqi, Li Liming, Liu Wen, Cai Yi, Zheng Guodong
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou 511436, China.
Guangdong Xinbaotang Biological Technology Co., Ltd., Jiangmen 529100, China.
Acta Biochim Biophys Sin (Shanghai). 2025 Jul 21. doi: 10.3724/abbs.2025113.
Nasopharyngeal carcinoma (NPC) ranks among the most prevalent malignancies, particularly in East Asia and Southeast Asia. Nobiletin (NOB), an exclusive polymethoxyflavonoid derived from citrus peel, exhibits diverse physiological properties, notably its potent anticancer activity. Kelch-like ECH-associated protein 1 (KEAP1), the repressor protein regulating the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, has emerged as a promising strategy for addressing oxidative stress in various diseases. The KEAP1/NRF2/ARE signal is a fundamental pathway within the cellular homeostatic defense system. This study robustly demonstrates the chemopreventive potential of NOB through comprehensive and assessments using subcutaneous tumor mouse models. Furthermore, our groundbreaking findings reveal that NOB effectively hinders the migration and invasion capacities of CNE-2 and 5-8F (NPC) cells in a dose- and time-dependent manner. Mechanistically, NOB, a potent KEAP1 activator, significantly disrupts the NRF2/ARE signaling pathway by accelerating the proteasomal degradation of NRF2 and suppressing its nuclear translocation. Consequently, this cascade reduces the expressions of ARE-driven genes and antioxidant enzymes, thereby increasing intracellular reactive oxygen species (ROS) levels and increasing antitumor immunity. Moreover, the sensitivity induced by NOB is markedly diminished in CNE-2 cells following the gene silencing of . These findings underscore the pivotal role of NOB in activating KEAP1. Overall, KEAP1 has emerged as a compelling target for potential malignancy treatment in nasopharyngeal carcinoma cell lines. Our results suggest the promising application of NOB as a natural sensitizer in chemotherapy, opening avenues for promising therapeutic interventions.
鼻咽癌（NPC）是最常见的恶性肿瘤之一，在东亚和东南亚地区尤为如此。诺必亭（NOB）是一种从柑橘皮中提取的独特多甲氧基黄酮，具有多种生理特性，尤其是其强大的抗癌活性。 Kelch样ECH相关蛋白1（KEAP1）是调节核因子红细胞2相关因子2（NRF2）转录因子的阻遏蛋白，已成为解决各种疾病中氧化应激的一种有前景的策略。KEAP1/NRF2/ARE信号是细胞内稳态防御系统中的一条基本途径。本研究通过使用皮下肿瘤小鼠模型进行全面评估，有力地证明了NOB的化学预防潜力。此外，我们的开创性发现表明，NOB以剂量和时间依赖性方式有效阻碍CNE-2和5-8F（NPC）细胞的迁移和侵袭能力。从机制上讲，NOB是一种有效的KEAP1激活剂，通过加速NRF2的蛋白酶体降解并抑制其核转位，显著破坏NRF2/ARE信号通路。因此，这一系列反应降低了ARE驱动基因和抗氧化酶的表达，从而增加细胞内活性氧（ROS）水平并增强抗肿瘤免疫力。此外，在基因沉默后，CNE-2细胞中由NOB诱导的敏感性明显降低。这些发现强调了NOB在激活KEAP1中的关键作用。总体而言，KEAP1已成为鼻咽癌细胞系潜在恶性肿瘤治疗的一个有吸引力的靶点。我们研究结果表明，NOB作为化疗中的一种天然增敏剂具有广阔的应用前景，为有前景的治疗干预开辟了道路。
