TRIAP1 Knockdown Sensitizes Non-small Cell Lung Cancer to Ionizing Radiation by Disrupting Redox Homeostasis

Overview

Journal Thorac Cancer

Specialties Oncology
Pulmonary Medicine

Date 2020 Feb 26

PMID 32096592

Citations 11

Authors

Chun-Cheng Hao

Jia-Ning Luo

Cui-Yang Xu

Xin-Yu Zhao

Zhen-Bin Zhong

Xiao-Nan Hu

Xiao-Ming Jin

Xiaofeng Ge

Affiliations

Soon will be listed here.

Abstract

Background: Radioresistance of some non-small cell lung cancer (NSCLC) types increases the risk of recurrence or metastasis in afflicted patients, following radiotherapy. As such, further improvements to NSCLC radiotherapy are needed. The expression of oncogene TP53-regulated inhibitor of apoptosis 1 (TRIAP1) in NSCLC is increased following irradiation. Furthermore, gene set enrichment analysis (GSEA) has suggested that TRIAP1 might be involved in maintaining redox homeostasis. This in turn might enhance cell radioresistance.

Methods: In this study we irradiated human NSCLC cell lines (A549 and H460), while knocking down TRIAP1, to determine whether a disrupted redox homeostasis could attenuate radioresistance.

Results: Irradiation notably increased both mRNA and protein levels of TRIAP1. In addition, TRIAP1 knockdown decreased the expression of several antioxidant proteins, including thioredoxin-related transmembrane protein (TMX) 1, TMX2, thioredoxin (TXN), glutaredoxin (GLRX) 2, GLRX3, peroxiredoxin (PRDX) 3, PRDX4, and PRDX6 in A549 and H460 cells. In addition, silencing TRIAP1 impaired the radiation-induced increase of the aforementioned proteins. Continuing along this line, we observed a radiation-induced reduction of cell viability and invasion, as well as increased apoptosis and intracellular reactive oxygen species following TRIAP1 knockdown.

Conclusions: In summary, we identified TRIAP1 as a key contributor to the radioresistance of NSCLC by maintaining redox homeostasis.

Citing Articles

Matrix-free human lung organoids derived from induced pluripotent stem cells to model lung injury.

Budeus B, Kroepel C, Stasch L, Klein D Stem Cell Res Ther. 2024; 15(1):468.

PMID: 39696649 PMC: 11657174. DOI: 10.1186/s13287-024-04106-3.

Circular RNA NFIX Functions as an Oncogene in Non-Small Cell Lung Cancer by Modulating the miR-214-3p/TRIAP1 Axis.

Liu G, Shi H, Zheng H, Kong W, Cheng X, Deng L Clin Respir J. 2024; 18(8):e13801.

PMID: 39135128 PMC: 11319089. DOI: 10.1111/crj.13801.

Two microRNAs of plasma-derived small extracellular vesicles as biomarkers for metastatic non-small cell lung cancer.

Geng N, Qi Y, Qin W, Li S, Jin H, Jiang Y BMC Pulm Med. 2023; 23(1):259.

PMID: 37452310 PMC: 10347730. DOI: 10.1186/s12890-023-02538-w.

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies.

Shen J, Wang Q, Mao Y, Gao W, Duan S MedComm (2020). 2023; 4(3):e288.

PMID: 37256211 PMC: 10225743. DOI: 10.1002/mco2.288.

The Role of Peroxiredoxins in Cancer Development.

Thapa P, Jiang H, Ding N, Hao Y, Alshahrani A, Wei Q Biology (Basel). 2023; 12(5).

PMID: 37237480 PMC: 10215932. DOI: 10.3390/biology12050666.

References

Kim J, Cho J, Kim E, Shin H, Hwang S, Song J . β-Apopicropodophyllin functions as a radiosensitizer targeting ER stress in non-small cell lung cancer. Biomed Pharmacother. 2019; 113:108769. DOI: 10.1016/j.biopha.2019.108769. View

Yoshihara E, Chen Z, Matsuo Y, Masutani H, Yodoi J . Thiol redox transitions by thioredoxin and thioredoxin-binding protein-2 in cell signaling. Methods Enzymol. 2010; 474:67-82. DOI: 10.1016/S0076-6879(10)74005-2. View

Wu H, Xing K, Lou M . Glutaredoxin 2 prevents H(2)O(2)-induced cell apoptosis by protecting complex I activity in the mitochondria. Biochim Biophys Acta. 2010; 1797(10):1705-15. PMC: 2964346. DOI: 10.1016/j.bbabio.2010.06.003. View

Andrysik Z, Kim J, Tan A, Espinosa J . A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation. Cell Rep. 2013; 3(5):1346-54. PMC: 3733554. DOI: 10.1016/j.celrep.2013.04.014. View

Wang H, Bouzakoura S, de Mey S, Jiang H, Law K, Dufait I . Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species. Oncotarget. 2017; 8(22):35728-35742. PMC: 5482612. DOI: 10.18632/oncotarget.16113. View

Li B, Chen M, Lu M, Xin-Xiang J, Meng-Xiong P, Jun-Wu M . Glutaredoxin 3 promotes migration and invasion via the Notch signalling pathway in oral squamous cell carcinoma. Free Radic Res. 2018; 52(4):390-401. DOI: 10.1080/10715762.2018.1435871. View

Zhang H, Zhang D, Ju T, Zhou J . The effect of postoperative radiotherapy on the survival of patients with resectable stage III-N2 non-small-cell lung cancer: a systematic review and meta-analysis. Neoplasma. 2019; 66(5):717-726. DOI: 10.4149/neo_2018_181213N965. View

Shin S, Cha H, Lee E, Lee S, Seo S, Jin H . Alteration of miRNA profiles by ionizing radiation in A549 human non-small cell lung cancer cells. Int J Oncol. 2009; 35(1):81-6. View

Yang H, Kim N, Seong K, Youn H, Youn B . Investigation of radiation-induced transcriptome profile of radioresistant non-small cell lung cancer A549 cells using RNA-seq. PLoS One. 2013; 8(3):e59319. PMC: 3606344. DOI: 10.1371/journal.pone.0059319. View

10.

Kakolyris S, Giatromanolaki A, Koukourakis M, Powis G, Souglakos J, Sivridis E . Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer. Clin Cancer Res. 2001; 7(10):3087-91. View

11.

Zhang H, Du Y, Zhang X, Lu J, Holmgren A . Glutaredoxin 2 reduces both thioredoxin 2 and thioredoxin 1 and protects cells from apoptosis induced by auranofin and 4-hydroxynonenal. Antioxid Redox Signal. 2013; 21(5):669-81. PMC: 4098818. DOI: 10.1089/ars.2013.5499. View

12.

Ketteler J, Panic A, Reis H, Wittka A, Maier P, Herskind C . Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1. J Clin Med. 2019; 8(3). PMC: 6462938. DOI: 10.3390/jcm8030348. View

13.

Adams C, Cazzanelli G, Rasul S, Hitchinson B, Hu Y, Coombes R . Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance. Oncol Rep. 2015; 34(1):415-22. DOI: 10.3892/or.2015.3988. View

14.

Cho S, Cinghu S, Yu J, Park W . Helicase-like transcription factor confers radiation resistance in cervical cancer through enhancing the DNA damage repair capacity. J Cancer Res Clin Oncol. 2010; 137(4):629-37. DOI: 10.1007/s00432-010-0925-5. View

15.

Lillig C, Lonn M, Enoksson M, Fernandes A, Holmgren A . Short interfering RNA-mediated silencing of glutaredoxin 2 increases the sensitivity of HeLa cells toward doxorubicin and phenylarsine oxide. Proc Natl Acad Sci U S A. 2004; 101(36):13227-32. PMC: 516552. DOI: 10.1073/pnas.0401896101. View

16.

Matsuo Y, Nishinaka Y, Suzuki S, Kojima M, Kizaka-Kondoh S, Kondo N . TMX, a human transmembrane oxidoreductase of the thioredoxin family: the possible role in disulfide-linked protein folding in the endoplasmic reticulum. Arch Biochem Biophys. 2004; 423(1):81-7. DOI: 10.1016/j.abb.2003.11.003. View

17.

He Y, Xu W, Xiao Y, Pan L, Chen G, Tang Y . Overexpression of Peroxiredoxin 6 (PRDX6) Promotes the Aggressive Phenotypes of Esophageal Squamous Cell Carcinoma. J Cancer. 2018; 9(21):3939-3949. PMC: 6218759. DOI: 10.7150/jca.26041. View

18.

Shah S, Rodriguez G, Musick A, Walters W, de Cordoba N, Barbarite E . Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR). Cancers (Basel). 2019; 11(2). PMC: 6406669. DOI: 10.3390/cancers11020159. View

19.

Cheng J, Chou C, Kuo M, Hsieh C . Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene. 2006; 25(53):7009-18. DOI: 10.1038/sj.onc.1209706. View

20.

Chen L, Huang C, Yang X, Zhang Q, Chen F . Prognostic roles of mRNA expression of peroxiredoxins in lung cancer. Onco Targets Ther. 2018; 11:8381-8388. PMC: 6267628. DOI: 10.2147/OTT.S181314. View