Knockdown of in NSCLC Induces CXCL8 Secretion

Overview

Journal Front Pharmacol

Date 2024 Feb 26

PMID 38405671

Authors

Ziyang He

Fangyi Li

Xinyi Zhang

Dacheng Gao

Zhiwen Zhang

Rui Xu

Xingguo Cao

Qiyuan Shan

Zhen Ren

Yali Liu

Zengguang Xu

Affiliations

Soon will be listed here.

Abstract

Non-small cell lung cancer (NSCLC) is the most common type of lung tumor; however, we lack effective early detection indicators and therapeutic targets. Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) is vital to initiate protein synthesis, acting as a scaffolding protein for the eukaryotic protein translation initiation factor complex, EIF4F, which regulates protein synthesis together with EIF4A, EIF4E, and other translation initiation factors. However, EIF4G1's function in NSCLC cancer is unclear. Herein, transcriptome sequencing showed that knockdown of in H1299 NSCLC cells upregulated the expression of various inflammation-related factors. Inflammatory cytokines were also significantly overexpressed in NSCLC tumor tissues, among which (encoding C-X-C motif chemokine ligand 8) showed the most significant changes in both in the transcriptome sequencing data and tumor tissues. We revealed that EIF4G1 regulates the protein level of TNF receptor superfamily member 10a (TNFRSF10A) resulting in activation of the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) pathways, which induces CXCL8 secretion, leading to targeted chemotaxis of immune cells. We verified that H1299 cells with knockdown showed increased chemotaxis compared with the control group and promoted increased chemotaxis of macrophages. These data suggested that EIF4G1 is an important molecule in the inflammatory response of cancer tissues in NSCLC.

References

Ashkenazi A . Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev. 2008; 19(3-4):325-31. DOI: 10.1016/j.cytogfr.2008.04.001. View

Li Y, Juergens R, Finley C, Swaminath A . Current and Future Treatment Options in the Management of Stage III NSCLC. J Thorac Oncol. 2023; 18(11):1478-1491. DOI: 10.1016/j.jtho.2023.08.011. View

Siegel R, Miller K, Fuchs H, Jemal A . Cancer statistics, 2022. CA Cancer J Clin. 2022; 72(1):7-33. DOI: 10.3322/caac.21708. View

Hsieh A, Liu Y, Edlind M, Ingolia N, Janes M, Sher A . The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012; 485(7396):55-61. PMC: 3663483. DOI: 10.1038/nature10912. View

Cambier S, Gouwy M, Proost P . The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol Immunol. 2023; 20(3):217-251. PMC: 9890491. DOI: 10.1038/s41423-023-00974-6. View

Li J, Xu P, Wu D, Guan M, Weng X, Lu Y . Hypoxic stress suppresses lung tumor-secreted exosomal miR101 to activate macrophages and induce inflammation. Cell Death Dis. 2021; 12(8):776. PMC: 8346509. DOI: 10.1038/s41419-021-04030-x. View

Stower H . Effective treatment of NSCLC. Nat Med. 2020; 26(10):1512. DOI: 10.1038/s41591-020-1106-y. View

Shi X, Wan Y, Wang N, Xiang J, Wang T, Yang X . Selection of a picomolar antibody that targets CXCR2-mediated neutrophil activation and alleviates EAE symptoms. Nat Commun. 2021; 12(1):2547. PMC: 8100106. DOI: 10.1038/s41467-021-22810-z. View

Mantovani A, Sozzani S, Locati M, Allavena P, Sica A . Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002; 23(11):549-55. DOI: 10.1016/s1471-4906(02)02302-5. View

10.

Jaiswal P, Koul S, Palanisamy N, Koul H . Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1): a target for cancer therapeutic intervention?. Cancer Cell Int. 2019; 19:224. PMC: 6717390. DOI: 10.1186/s12935-019-0947-2. View

11.

Brito Querido J, Diaz-Lopez I, Ramakrishnan V . The molecular basis of translation initiation and its regulation in eukaryotes. Nat Rev Mol Cell Biol. 2023; 25(3):168-186. DOI: 10.1038/s41580-023-00624-9. View

12.

Fan S, Li Y, Yue P, Khuri F, Sun S . The eIF4E/eIF4G interaction inhibitor 4EGI-1 augments TRAIL-mediated apoptosis through c-FLIP Down-regulation and DR5 induction independent of inhibition of cap-dependent protein translation. Neoplasia. 2010; 12(4):346-56. PMC: 2847742. DOI: 10.1593/neo.10144. View

13.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

14.

Yang H, Zhang Q, Xu M, Wang L, Chen X, Feng Y . CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer. 2020; 19(1):41. PMC: 7045401. DOI: 10.1186/s12943-020-01165-x. View

15.

Pittet M, Michielin O, Migliorini D . Clinical relevance of tumour-associated macrophages. Nat Rev Clin Oncol. 2022; 19(6):402-421. DOI: 10.1038/s41571-022-00620-6. View

16.

Liu Y, Cui J, Hoffman A, Hu J . Eukaryotic translation initiation factor eIF4G2 opens novel paths for protein synthesis in development, apoptosis and cell differentiation. Cell Prolif. 2022; 56(3):e13367. PMC: 9977666. DOI: 10.1111/cpr.13367. View

17.

Capece D, Verzella D, Flati I, Arboretto P, Cornice J, Franzoso G . NF-κB: blending metabolism, immunity, and inflammation. Trends Immunol. 2022; 43(9):757-775. DOI: 10.1016/j.it.2022.07.004. View

18.

Pimentel J, Zhou J, Wu G . The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer. Cancers (Basel). 2023; 15(10). PMC: 10216286. DOI: 10.3390/cancers15102752. View

19.

Liu W, Wang L, Zhou F, Liu S, Wang W, Zhao E . Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC. Drug Resist Updat. 2023; 70:100987. DOI: 10.1016/j.drup.2023.100987. View

20.

Legler K, Hauser C, Egberts J, Willms A, Heneweer C, Boretius S . The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells. Cell Death Dis. 2018; 9(5):445. PMC: 5906476. DOI: 10.1038/s41419-018-0478-0. View