دورية أكاديمية
أعرض في EDS

Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC.

التفاصيل البيبلوغرافية
العنوان: Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC.
المؤلفون: Liu WJ; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Wang L; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Zhou FM; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Liu SW; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Wang W; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Zhao EJ; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Yao QJ; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Li W; Department of Pathology, Affiliated Drum Tower Hospital Nanjing University Medical School, Nanjing 210000, China., Zhao YQ; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China., Shi Z; Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, 510632, China., Qiu JG; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China. Electronic address: jiangeqiu@zzu.edu.cn., Jiang BH; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China. Electronic address: binghjiang@zzu.edu.cn.
المصدر: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2023 Sep; Vol. 70, pp. 100987. Date of Electronic Publication: 2023 Jun 22.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Churchill Livingstone Country of Publication: Scotland NLM ID: 9815369 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-2084 (Electronic) Linking ISSN: 13687646 NLM ISO Abbreviation: Drug Resist Updat Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Edinburgh ; Philadelphia : Churchill Livingstone, c1998-
مواضيع طبية MeSH: Carcinoma, Non-Small-Cell Lung*/drug therapy , Carcinoma, Non-Small-Cell Lung*/genetics , Lung Neoplasms*/drug therapy , Lung Neoplasms*/genetics , Tyrosine Kinase Inhibitors*/pharmacology, Humans ; Carcinogenesis ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; ErbB Receptors ; Gefitinib/pharmacology ; Gefitinib/therapeutic use ; Interleukin-8/genetics ; Mutation ; NADPH Oxidase 4/genetics
مستخلص: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for human non-small-cell lung cancer (NSCLC) treatment. However, acquired resistance to EGFR-TKIs is the major barrier of treatment success, and new resistance mechanism remains to be elucidated. In this study, we found that elevated NADPH oxidase 4 (NOX4) expression was associated with acquired EGFR-TKIs resistance. Gefitinib is the first-generation FDA-approved EGFR-TKI, and osimertinib is the third-generation FDA-approved EGFR-TKI. We demonstrated that NOX4 knockdown in the EGFR-TKI resistant cells enabled the cells to become sensitive to gefitinib and osimertinib treatment, while forced expression of NOX4 in the sensitive parental cells was sufficient to induce resistance to gefitinib and osimertinib in the cells. To elucidate the mechanism of NOX4 upregulation in increasing TKIs resistance, we found that knockdown of NOX4 significantly down-regulated the expression of transcription factor YY1. YY1 bound directly to the promoter region of IL-8 to transcriptionally activate IL-8 expression. Interestingly, knockdown of NOX4 and IL-8 decreased programmed death ligand 1 (PD-L1) expression, which provide new insight on TKIs resistance and immune escape. We found that patients with higher NOX4 and IL-8 expression levels showed a shorter survival time compared to those with lower NOX4 and IL-8 expression levels in response to the anti-PD-L1 therapy. Knockdown of NOX4, YY1 or IL-8 alone inhibited angiogenesis and tumor growth. Furthermore, the combination of NOX4 inhibitor GKT137831 and gefitinib had synergistic effect to inhibit cell proliferation and tumor growth and to increase cellular apoptosis. These findings demonstrated that NOX4 and YY1 were essential for mediating the acquired EGFR-TKIs resistance. IL-8 and PD-L1 are two downstream targets of NOX4 to regulate TKIs resistance and immunotherapy. These molecules may be used as potential new biomarkers and therapeutic targets for overcoming TKIs resistance in the future.
Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
فهرسة مساهمة: Keywords: Gefitinib resistance; IL-8; NOX4; PD-L1; Tumor growth
المشرفين على المادة: 0 (CD274 protein, human)
EC 2.7.10.1 (EGFR protein, human)
EC 2.7.10.1 (ErbB Receptors)
S65743JHBS (Gefitinib)
0 (Interleukin-8)
EC 1.6.3.- (NADPH Oxidase 4)
EC 1.6.3.- (NOX4 protein, human)
3C06JJ0Z2O (osimertinib)
0 (Tyrosine Kinase Inhibitors)
تواريخ الأحداث: Date Created: 20230701 Date Completed: 20230815 Latest Revision: 20231213
رمز التحديث: 20231215
DOI: 10.1016/j.drup.2023.100987
PMID: 37392558
قاعدة البيانات: MEDLINE
الوصف
تدمد:1532-2084
DOI:10.1016/j.drup.2023.100987