中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 2
Feb.  2022
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2022  >  38(2): 372-380

Role of thioredoxin reductase 1 in multidrug resistance caused by reactive oxygen species-related cell apoptosis in hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2022.02.022
  • a.

    Key Laboratory of Multiple Organ Transplantation, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China

  • b.

    Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, China

More Information
  • Corresponding author: ZHANG Aibin, zhangaibin@zju.edu.cn
  • Received Date: 2021-08-05
  • Accepted Date: 2021-09-06
  • Published Date: 2022-02-20
    Abstract
  •   Objective  Drug resistance is the main cause of chemotherapy failure in hepatocellular carcinoma (HCC), and thioredoxin reductase 1 (TXNRD1), as a major influencing factor for reactive oxygen species (ROS) metabolism, has been proven to be associated with the poor prognosis of patients with HCC. This study aims to explore the role of TXNRD1 in the mechanism of multidrug resistance in HCC.  Methods  BEL/FU cells in BEL-7402 cell line were selected as the multidrug-resistant cell line. The siRNA was used for the intervention of TXNRD1 expression; quantitative real-time PCR and Western blotting were used to measure the expression of TXNRD1; CCK-8 assay and flow cytometry were used to evaluate the effect of TXNRD1 on hepatocyte ROS accumulation, resistance to 5-fluorouracil (5-Fu) and doxorubicin (DOX), and apoptosis in vitro; a xenograft tumor model was established to investigate the effect of auranofin (AUR) on drug resistance in vivo. The two-independent-samples t test was used for comparison of continuous data between two groups.  Results  As a multidrug-resistant HCC cell line, BEL/Fu showed high mRNA and protein expression levels of TXNRD1 (both P < 0.05). Compared with 5-Fu or DOX treatment alone, the TXNRD1 inhibitor AUR combined with 5-Fu or DOX had had a significant reduction in the number of colony formation (P < 0.01) and a significant increase in apoptosis ratio (P < 0.001). The ROS scavenger N-acetylcysteine (NAC) significantly weakened the effect of TXNRD1 knockdown by siRNA on the drug resistance of BEL/Fu cells, and the application of NAC effectively reduced the apoptosis ratio of cells after siRNA interference (P < 0.001). Animal experiments also confirmed that compared with the nude mice treated with 5-Fu alone, the nude mice treated with 5-Fu and AUR had a significantly lower tumor mass (P < 0.001) and a significantly smaller tumor volume (P < 0.001).  Conclusion  TXNRD1 plays an important role in the drug resistance of HCC, and inhibition of its level in cells can effectively improve drug resistance. As a TXNRD1 inhibitor, AUR has great application prospects in the multimodality therapy for HCC.

     

    • FullText(HTML)
  • loading
    • References(28)
  • [1]
    SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
    [2]
    CHEN Z, XIE H, HU M, et al. Recent progress in treatment of hepatocellular carcinoma[J]. Am J Cancer Res, 2020, 10(9): 2993-3036.
    [3]
    SZAKÁCS G, PATERSON JK, LUDWIG JA, et al. Targeting multidrug resistance in cancer[J]. Nat Rev Drug Discov, 2006, 5(3): 219-234. DOI: 10.1038/nrd1984.
    [4]
    BUKOWSKI K, KCIUK M, KONTEK R. Mechanisms of multidrug resistance in cancer chemotherapy[J]. Int J Mol Sci, 2020, 21(9): 3233. DOI: 10.3390/ijms21093233.
    [5]
    KLAUNIG JE. Oxidative stress and cancer[J]. Curr Pharm Des, 2018, 24(40): 4771-4778. DOI: 10.2174/1381612825666190215121712.
    [6]
    KUDRYAVTSEVA AV, KRASNOV GS, DMITRIEV AA, et al. Mitochondrial dysfunction and oxidative stress in aging and cancer[J]. Oncotarget, 2016, 7(29): 44879-44905. DOI: 10.18632/oncotarget.9821.
    [7]
    JAKUBCZYK K, DEC K, KAŁDUŃSKA J, et al. Reactive oxygen species-sources, functions, oxidative damage[J]. Pol Merkur Lekarski, 2020, 48(284): 124-127.
    [8]
    AKIN-BALI DF, AL-KHAFAJI K, AKTAS SH, et al. Bioinformatic and computational analysis for predominant mutations of the Nrf2/Keap1 complex in pediatric leukemia[J]. J Biomol Struct Dyn, 2021, 39(12): 4290-4303. DOI: 10.1080/07391102.2020.1775702.
    [9]
    GAO Q, ZHANG G, ZHENG Y, et al. SLC27A5 deficiency activates NRF2/TXNRD1 pathway by increased lipid peroxidation in HCC[J]. Cell Death Differ, 2020, 27(3): 1086-1104. DOI: 10.1038/s41418-019-0399-1.
    [10]
    HUANG S, ZHU X, KE Y, et al. LncRNA FTX inhibition restrains osteosarcoma proliferation and migration via modulating miR-320a/TXNRD1[J]. Cancer Biol Ther, 2020, 21(4): 379-387. DOI: 10.1080/15384047.2019.1702405.
    [11]
    PARK N, CHUN YJ. Auranofin promotes mitochondrial apoptosis by inducing annexin A5 expression and translocation in human prostate cancer cells[J]. J Toxicol Environ Health A, 2014, 77(22-24): 1467-1476. DOI: 10.1080/15287394.2014.955834.
    [12]
    FU B, MENG W, ZENG X, et al. TXNRD1 is an unfavorable prognostic factor for patients with hepatocellular carcinoma[J]. Biomed Res Int, 2017, 2017: 4698167. DOI: 10.1155/2017/4698167.
    [13]
    PRASAD S, GUPTA SC, TYAGI AK. Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals[J]. Cancer Lett, 2017, 387: 95-105. DOI: 10.1016/j.canlet.2016.03.042.
    [14]
    LIU N, GUO Z, XIA X, et al. Auranofin lethality to prostate cancer includes inhibition of proteasomal deubiquitinases and disrupted androgen receptor signaling[J]. Eur J Pharmacol, 2019, 846: 1-11. DOI: 10.1016/j.ejphar.2019.01.004.
    [15]
    LIOU GY, STORZ P. Reactive oxygen species in cancer[J]. Free Radic Res, 2010, 44(5): 479-496. DOI: 10.3109/10715761003667554.
    [16]
    SEIFRIED HE, ANDERSON DE, SORKIN BC, et al. Free radicals: The pros and cons of antioxidants. Executive summary report[J]. J Nutr, 2004, 134(11): 3143S-3163S. DOI: 10.1093/jn/134.11.3143S.
    [17]
    SUN C, ZHANG H, MA XF, et al. Isoliquiritigenin enhances radiosensitivity of HepG2 cells via disturbance of redox status[J]. Cell Biochem Biophys, 2013, 65(3): 433-444. DOI: 10.1007/s12013-012-9447-x.
    [18]
    LING S, LI J, SHAN Q, et al. USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway[J]. Mol Oncol, 2017, 11(6): 682-695. DOI: 10.1002/1878-0261.12067.
    [19]
    ZHOU Y, WANG Y, ZHOU W, et al. YAP promotes multi-drug resistance and inhibits autophagy-related cell death in hepatocellular carcinoma via the RAC1-ROS-mTOR pathway[J]. Cancer Cell Int, 2019, 19: 179. DOI: 10.1186/s12935-019-0898-7.
    [20]
    KIM NH, PARK HJ, OH MK, et al. Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells[J]. BMB Rep, 2013, 46(1): 59-64. DOI: 10.5483/bmbrep.2013.46.1.123.
    [21]
    HWANG-BO H, JEONG JW, HAN MH, et al. Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species[J]. Gen Physiol Biophys, 2017, 36(2): 117-128. DOI: 10.4149/gpb_2016043.
    [22]
    LIU JJ, LIU Q, WEI HL, et al. Inhibition of thioredoxin reductase by auranofin induces apoptosis in adriamycin-resistant human K562 chronic myeloid leukemia cells[J]. Pharmazie, 2011, 66(6): 440-444.
    [23]
    ZHENG Y, LIU Y, ZHAO S, et al. Large-scale analysis reveals a novel risk score to predict overall survival in hepatocellular carcinoma[J]. Cancer Manag Res, 2018, 10: 6079-6096. DOI: 10.2147/CMAR.S181396.
    [24]
    CARLSON BA, YOO MH, TOBE R, et al. Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis[J]. Carcinogenesis, 2012, 33(9): 1806-1813. DOI: 10.1093/carcin/bgs230.
    [25]
    OZBEN T. Antioxidant supplementation on cancer risk and during cancer therapy: An update[J]. Curr Top Med Chem, 2015, 15(2): 170-178. DOI: 10.2174/1568026615666141209160918
    [26]
    CALAF GM, AGUAYO F, SERGI CM, et al. Antioxidants and cancer: Theories, techniques, and trials in preventing cancer[J]. Oxid Med Cell Longev, 2018, 2018: 5363064. DOI: 10.1155/2018/5363064.
    [27]
    KLEIN EA, THOMPSON IM Jr, TANGEN CM, et al. Vitamin E and the risk of prostate cancer: The selenium and vitamin E Cancer Prevention Trial (SELECT)[J]. JAMA, 2011, 306(14): 1549-1556. DOI: 10.1001/jama.2011.1437.
    [28]
    ARNÉR E. Targeting the selenoprotein thioredoxin reductase 1 for anticancer therapy[J]. Adv Cancer Res, 2017, 136: 139-151. DOI: 10.1016/bs.acr.2017.07.005.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(8)  / Tables(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (596) PDF downloads(56) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return