药学学报, 2021, 56(5): 1352-1359
引用本文:
余娇娇, 张诚, 向昱瑾, 胡卓伟, 崔冰*, 花芳*. TRIB3激活NRF2促进肺癌细胞增殖并抑制其凋亡[J]. 药学学报, 2021, 56(5): 1352-1359.
YU Jiao-jiao, ZHANG Cheng, XIANG Yu-jin, HU Zhuo-wei, CUI Bing*, HUA Fang*. TRIB3 promotes lung cancer cell survival and inhibits apoptosis through NRF2 activation[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1352-1359.

TRIB3激活NRF2促进肺癌细胞增殖并抑制其凋亡
余娇娇, 张诚, 向昱瑾, 胡卓伟, 崔冰*, 花芳*
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 中国医学科学院代谢紊乱和肿瘤发生相关机制和靶点发现重点实验室, 北京 100050
摘要:
核转录因子NRF2(nuclear factor erythroid 2-related factor 2)是调控细胞氧化还原稳态的重要蛋白。NRF2异常激活所致抗氧化能力提高是导致肿瘤恶性进程和耐药形成的关键原因。本文旨在探究应激蛋白TRIB3(tribbles homolog 3)调节氧化应激,促进肺癌细胞增殖并抑制其凋亡的分子机制。本研究首先对癌症基因组图谱(the cancer genome atlas,TCGA)数据库中576个肺癌临床样本进行生物信息学分析,发现TRIB3高表达肺癌患者NRF2-ARE(antioxidant response element)信号通路活化。双荧光素酶报告基因实验和实时荧光定量PCR检测证实TRIB3促进核转录因子NRF2的转录激活活性,上调其下游靶基因表达。机制及生物学验证研究结果表明,TRIB3主要通过干扰KEAP1(kelch-like ECH-associated protein-1)-NRF2相互作用,进而增强NRF2稳定性。敲低TRIB3促进活性氧自由基(reactive oxygen species,ROS)产生,抑制细胞生长并增加卡铂引起的细胞凋亡;过表达NRF2可逆转敲低TRIB3产生的抑增殖、促凋亡效应;而在NRF2敲低的肿瘤细胞中,抑制TRIB3并不影响肿瘤细胞的增殖和凋亡水平。综上,本研究表明,应激蛋白TRIB3抑制KEAP1-NRF2相互作用,继而上调NRF2转录激活活性,促进肿瘤增殖并降低化疗药物敏感性;靶向TRIB3-NRF2信号轴可能成为治疗肺癌的新策略。
关键词:    TRIB3      氧化应激      蛋白相互作用      NRF2      增殖      凋亡     
TRIB3 promotes lung cancer cell survival and inhibits apoptosis through NRF2 activation
YU Jiao-jiao, ZHANG Cheng, XIANG Yu-jin, HU Zhuo-wei, CUI Bing*, HUA Fang*
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
The nuclear transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in maintaining cellular redox homeostasis. The aberrant NRF2 signaling confers enhanced antioxidant capacity, which is linked to tumor progression and therapeutic resistance. The current study investigates the biological effects and molecular mechanism of tribbles homolog 3 (TRIB3), a stress-induced protein, in regulating cell survival and apoptosis in lung cancer. This study first performed the RNA sequencing data analysis with 576 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database. The NRF2-antioxidant response element (ARE) signature was enriched in patients with high TRIB3 expression. Dual-luciferase reporter assay and real-time quantitative polymerase chain reaction (PCR) were used to confirm the effect of TRIB3 on the kelch-like ECH-associated protein-1 (KEAP1)-NRF2 pathway. Abrogation of TRIB3 impaired NRF2 transcriptional activity and reduced the expression of its target genes. Moreover, TRIB3 enhanced NRF2 stability via blocking KEAP1-NRF2 interaction. TRIB3-depletion promoted reactive oxygen species (ROS) production, restrained cell proliferation, and enhanced carboplatin-induced apoptosis. In addition, NRF2 overexpression recovered the tumor inhibition effect of TRIB3-depletion. Consistently, TRIB3 failed to modulate apoptosis in NRF2 depletion cells. In summary, this study shows that TRIB3 inhibits the KEAP1-NRF2 interaction and upregulates the transcriptional activity of NRF2, thereby promoting lung cancer cell proliferation and reducing the sensitivity to chemotherapy. Targeting the TRIB3-NRF2 signal axis may become a new strategy for ROS homeostasis and lung cancer treatment.
Key words:    TRIB3    oxidative stress    protein-protein interaction    NRF2    proliferation    apoptosis   
收稿日期: 2021-02-05
DOI: 10.16438/j.0513-4870.2021-0187
基金项目: 国家自然科学基金资助项目(81973344,81874316,81703564);中国医学科学院医学与健康科技创新工程(2016-I2M-1-007,2016-I2M-3-008);中国医学科学院中央级公益性科研院所基本科研业务费(2017PT31046,2018RC350004);北京高校卓越青年科学家项目(BJJWZYJH01201910023028).
通讯作者: 崔冰,Tel:86-10-83161187,E-mail:cuibing@imm.ac.cn;花芳,E-mail:huafang@imm.ac.cn
Email: cuibing@imm.ac.cn;huafang@imm.ac.cn
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