Recombinant Newcastle disease virus rL-RVG induces ferroptosis of gastric cancer cells through inhibiting Nrf2-GCLC-GPX4 pathway

Kewen GONG; Yidu TIAN; Yingjue HE; Yang LI; Xuefeng BU

doi:10.16016/j.2097-0927.202310051

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Recombinant Newcastle disease virus rL-RVG induces ferroptosis of gastric cancer cells through inhibiting Nrf2-GCLC-GPX4 pathway

Basic Medicine | 更新时间：2026-01-09

- Recombinant Newcastle disease virus rL-RVG induces ferroptosis of gastric cancer cells through inhibiting Nrf2-GCLC-GPX4 pathway
- Journal of Army Medical University Vol. 46, Issue 13, Pages: 1485-1493(2024)
- 作者机构：
  
  1.212000 江苏镇江，江苏大学附属人民医院普外科
  2.212000 江苏镇江，江苏大学附属人民医院呼吸内科
- 作者简介：
- 基金信息：
  
  the Science and Technology Innovation Fund of Zhenjiang City(SH2023004)
- DOI：10.16016/j.2097-0927.202310051
  CLC： R394.3;R73-362;R735.2
- Received：13 October 2023，
  
  Revised：2023-12-26，
  
  Published：15 July 2024
- 稿件说明：
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Kewen GONG, Yidu TIAN, Yingjue HE, et al. Recombinant Newcastle disease virus rL-RVG induces ferroptosis of gastric cancer cells through inhibiting Nrf2-GCLC-GPX4 pathway[J]. Journal of Army Medical University, 2024, 46(13): 1485-1493.
DOI：

Kewen GONG, Yidu TIAN, Yingjue HE, et al. Recombinant Newcastle disease virus rL-RVG induces ferroptosis of gastric cancer cells through inhibiting Nrf2-GCLC-GPX4 pathway[J]. Journal of Army Medical University, 2024, 46(13): 1485-1493. DOI： 10.16016/j.2097-0927.202310051.

摘要

目的

探讨重组新城疫病毒(recombinant Newcastle disease virus，rL-RVG)是否通过Nrf2-GCLC-GPX4通路引发胃癌细胞铁死亡。

方法

培养人胃癌HGC-27细胞，分别用rL-RVG、新城疫病毒(Newcastle disease virus，NDV)、PBS溶液(对照组)处理HGC-27细胞后，用CCK-8、Transwell侵袭、细胞划痕实验检测胃癌HGC-27细胞的增殖、侵袭、迁移能力。加入铁死亡促进剂(erastin)、核因子E2相关因子2(nuclear factor E2 related factor 2，Nrf2)促进剂(TBHQ)及抑制剂(ML385)作为干预组，脂质氧化试剂盒检测各组丙二醛(malondialdehyde，MDA)含量；DCFH-DA荧光探针及流式细胞仪检测活性氧(reactive oxygen species，ROS)的含量；Western blot、免疫荧光法检测Nrf2-GCLC-GPX4通路相关蛋白表达情况。

结果

与对照组比较，rL-RVG和NDV处理后，细胞的存活率均下降，呈剂量、时间依赖性，且rL-RVG处理组较为显著(

＜0.05)；NDV和rL-RVG处理组胃癌HGC-27细胞迁移、侵袭能力均受到抑制，后者较前者抑制更明显(

＜0.05)；与对照组比较，病毒组Nrf2、GCLC、SLC7A11、GPX4蛋白表达下降(

＜0.05)，MDA水平、ROS相对表达量上升(

＜0.05)，rL-RVG组上升或下降的趋势较NDV组明显，且erastin组SLC7A11、GPX4蛋白表达下降(

＜0.05)；与对照组比较，TBHQ组、ML385组Nrf2、GCLC、SLC7A11、GPX4蛋白表达分别上升、下降(

＜0.05)，MDA水平、ROS相对表达量分别下降、上升(

＜0.05)；与rL-RVG组比较，rL-RVG+TBHQ组、rL-RVG+ML385组Nrf2、GCLC、SLC7A11、GPX4蛋白表达分别上升、下降(

＜0.05)，MDA水平、ROS相对表达量分别下降、上升(

＜0.05)。

结论

重组新城疫病毒(rL-RVG)可通过Nrf2-GCLC-GPX4通路诱导胃癌细胞铁死亡的发生，抑制肿瘤细胞的生长。

Abstract

Objective

To investigate whether recombinant Newcastle disease virus (rL-RVG) induces iron death in gastric cancer cells through Nrf2-GCLC-GPX4 pathway.

Methods

After human gastric cancer HGC-27 cells were treated with rL-RVG

Newcastle disease virus (NDV) and PBS solution (control group)

respectively

cell proliferation

invasion and migration were detected by CCK-8 assay and Transwell invasion assay and cell scratch test. Ferroptosis accelerator (erastin)

and nuclear factor E2 related factor 2 (Nrf2) accelerator (TBHQ) and inhibitor (ML385) were added respectively as controls. The content of malondialdehyde (MDA) in each treatment group was detected by lipid oxidation kit. The content of reactive oxygen species (ROS) was detected by DCFH-DA fluorescent probe and flow cytometry. Western blotting and immunofluorescence assay were employed to measure the expression levels of Nrf2-GCLC-GPX4 pathway related proteins.

Results

Compared with the control group

the survival rate of HGC-27 cells were significantly decreased after rL-RVG and NDV treatment in a dose- and time-dependent manner

and the effect was more significant in the rL-RVG treatment group (

0.05). The migration and invasion abilities of HGC-27 cells were obviously inhibited in the NDV and rL-RVG treatment groups

and the latter had more notable inhibition than the former. The protein levels of Nrf2

GCLC

SLC7A11 and GPX4 were statistically decreased (

0.05)

and the contents of MDA and ROS were increased (

0.05) in the virus treatment groups than the control group

with the increasing or decreasing trend more significant in the rL-RVG group than the NDV group. What's more

the protein levels of SLC7A11 and GPX4 were decreased in the erastin group (

0.05). Compared with the control group

those of Nrf2

GCLC

SLC7A11 and GPX4 were increased in the TBHQ group and decreased in the ML385 group (

0.05)

while the contents of MDA and ROS were decreased and increased respectively in the above 2 groups (

0.05). Compared with the rL-RVG group

the rL-RVG+TBHQ group and rL-RVG+ML385 group had enhanced and reduced protein expressio of Nrf2

GCLC

SLC7A11 and GPX4

respectively (

0.05)

while the contents of MDA and ROS were in opposite trends (

0.05).

Conclusion

rL-RVG can induce ferroptosis of gastric cancer cells through Nrf2-GCLC-GPX4 pathway

and then inhibit the growth of tumor cells.

关键词

Keywords

references

SUNG H, FERLAY J, SIEGEL R L, 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.

赫捷, 陈万青, 李兆申, 等. 中国胃癌筛查与早诊早治指南(2022, 北京)[J]. 中国肿瘤, 2022, 31(7): 488-527. DOI: 10.11735/j.issn.1004-0242.2022.07.A002.

HE J, CHEN W Q, LI Z S, et al . China guideline for the screening, early detection and early treatment of gastric cancer(2022, Beijing)[J ] . China Cancer, 2022, 31(7): 488-527. DOI: 10.11735/j.issn.1004-0242.2022.07.A002.

DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J ] . Cell, 2012, 149(5): 1060-1072. DOI: 10.1016/j.cell.2012.03.042.

JIANG X J, STOCKWELL B, CONRAD M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282. DOI: 10.1038/s41580-020-00324-8.

DÄCHERT J, EHRENFELD V, HABERMANN K, et al . Targeting ferroptosis in rhabdomyosarcoma cells[J ] . Int J Cancer, 2020, 146(2): 510-520. DOI: 10.1002/ijc.32496.

SHIN D, KIM E H, LEE J, et al . Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer[J ] . Free Radic Biol Med, 2018, 129: 454-462. DOI: 10.1016/j.freeradbiomed.2018.10.426.

LU J, ZHAO Y N, LIU M T, et al . Toward improved human health: Nrf2 plays a critical role in regulating ferroptosis[J ] . Food Funct, 2021, 12(20): 9583-9606. DOI: 10.1039/d1fo01036k.

LIAN G J, GNANAPRAKASAM J R, WANG T T, et al . Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation[J ] . eLife, 2018, 7: e36158. DOI: 10.7554/eLife.36158..

SONG X H, LONG D X. Nrf2 and ferroptosis: a new research direction for neurodegenerative diseases[J]. Front Neurosci, 2020, 14: 267. DOI: 10.3389/fnins.2020.00267.

HE F, ANTONUCCI L, KARIN M. NRF 2 as a regulator of cell metabolism and inflammation in cancer[J ] . Carcinogenesis, 2020, 41(4): 405-416. DOI: 10.1093/carcin/bgaa039.

WANG X M, WANG Y L, HUANG D M, et al . Astragaloside Ⅳ regulates the ferroptosis signaling pathway via the Nrf2/SLC7A11/GPX4 axis to inhibit PM 2.5 -mediated lung injury in mice[J ] . Int Immunopharmacol, 2022, 112: 109186. DOI: 10.1016/j.intimp.2022.109186..

BURMAN B, PESCI G, ZAMARIN D. Newcastle disease virus at the forefront of cancer immunotherapy[J]. Cancers(Basel), 2020, 12(12): 3552. DOI: 10.3390/cancers12123552.

KAN X J, YIN Y C, SONG C P, et al . Newcastle-disease-virus-induced ferroptosis through nutrient deprivation and ferritinophagy in tumor cells[J ] . iScience, 2021, 24(8): 102837. DOI: 10.1016/j.isci.2021.102837.

BU X F, ZHAO Y H, ZHANG Z J, et al . Recombinant Newcastle disease virus(rL-RVG) triggers autophagy and apoptosis in gastric carcinoma cells by inducing ER stress[J ] . Am J Cancer Res, 2016, 6(5): 924-936. DOI: 2156-6976/ajcr0025130.

张珍珍, 李洋, 高生宝, 等. 重组新城疫病毒rL-RVG抑制人肺腺癌细胞系增殖[J]. 基础医学与临床, 2023, 43(10): 1549-1556. . DOI: 10.16352/j.issn.1001-6325.2023.10.1549.

ZHANG Z Z, LI Y, GAO S B, et al . Recombinant Newcastle virus rL-RVG inhibits proliferation of human lung adenocarcinoma cell lines[J ] . Basic Clin Med, 2023, 43(10): 1549-1556. . DOI: 10.16352/j.issn.1001-6325.2023.10.1549.

GU R J, XIA Y W, LI P F, et al . Ferroptosis and its role in gastric cancer[J ] . Front Cell Dev Biol, 2022, 10: 860344. DOI: 10.3389/fcell.2022.860344.

SMYTH E C, NILSSON M, GRABSCH H I, et al . Gastric cancer[J ] . Lancet, 2020, 396(10251): 635-648. DOI: 10.1016/S0140-6736(20)31288-5.

MACHLOWSKA J, BAJ J, SITARZ M, et al . Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies[J ] . Int J Mol Sci, 2020, 21(11): 4012. DOI: 10.3390/ijms21114012.

SCHIRRMACHER V. Molecular mechanisms of anti-neoplastic and immune stimulatory properties of oncolytic Newcastle disease virus[J]. Biomedicines, 2022, 10(3): 562. DOI: 10.3390/biomedicines10030562.

MENG Q X, HE J, ZHONG L P, et al . Advances in the study of antitumour immunotherapy for Newcastle disease virus[J ] . Int J Med Sci, 2021, 18(11): 2294-2302. DOI: 10.7150/ijms.59185.

尹超云, 张垚, 陈振威, 等. 重组新城疫病毒IL29抑制人胃癌细胞系BGC的增殖与迁移[J]. 基础医学与临床, 2020, 40(3): 368-373. DOI: 10.3969/j.issn.1001-6325.2020.03.021.

YIN C Y, ZHANG Y, CHEN Z W, et al . rL-IL29 inhibits proliferation and migration of human gastric cancer cell line BGC[J ] . Basic Clin Med, 2020, 40(3): 368-373. DOI: 10.3969/j.issn.1001-6325.2020.03.021.

LI M T, HE Y L, PENG C, et al . Erianin inhibits human cervical cancer cell through regulation of tumor protein p53 via the extracellular signal-regulated kinase signaling pathway[J ] . Oncol Lett, 2018, 16(4): 5006-5012. DOI: 10.3892/ol.2018.9267.

ZHAO Y N, LU J, MAO A K, et al . Autophagy inhibition plays a protective role in ferroptosis induced by alcohol via the p62-Keap1-Nrf2 pathway[J ] . J Agric Food Chem, 2021, 69(33): 9671-9683. DOI: 10.1021/acs.jafc.1c03751.

TANG D L, CHEN X, KANG R, et al . Ferroptosis: molecular mechanisms and health implications[J ] . Cell Res, 2021, 31(2): 107-125. DOI: 10.1038/s41422-020-00441-1.

CHEN P, WU Q B, FENG J, et al . Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis[J ] . Signal Transduct Target Ther, 2020, 5(1): 51. DOI: 10.1038/s41392-020-0149-3..

WEI R R, ZHAO Y Q, WANG J, et al . Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells[J ] . Int J Biol Sci, 2021, 17(11): 2703-2717. DOI: 10.7150/ijbs.59404.

XU J C, TIAN X Y, HAN R, et al . Erianin inhibits oral cancer cell growth, migration, and invasion via the Nrf2/HO-1/GPX4 pathway[J ] . Asian Pac J Trop Biomed, 2022, 12(10): 437-445. DOI: 10.4103/2221-1691.357743.

WANG Y L, YAN S, LIU X M, et al . PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway[J ] . Cell Death Differ, 2022, 29(10): 1982-1995. DOI: 10.1038/s41418-022-00990-5.

URSINI F, MAIORINO M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4[J]. Free Radic Biol Med, 2020, 152: 175-185. DOI: 10.1016/j.freeradbiomed.2020.02.027.

KOPPULA P, ZHUANG L, GAN B Y. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620. DOI: 10.1007/s13238-020-00789-5.

FORCINA G C, DIXON S J. GPX4 at the crossroads of lipid homeostasis and ferroptosis[J]. Proteomics, 2019, 19(18): e1800311. DOI: 10.1002/pmic.201800311.

KAJARABILLE N, LATUNDE-DADA G O. Programmed cell-death by ferroptosis: antioxidants as mitigators[J]. Int J Mol Sci, 2019, 20(19): 4968. DOI: 10.3390/ijms20194968.

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