OSGIN1 is a Novel TUBB3 Regulator That Promotes Tumor Progression and Gefitinib Resistance in Non-small Cell Lung Cancer

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2023 Aug 30

PMID 37646890

Authors

Xiaomeng Xie

Kyle Vaughn Laster

Jian Li

Wenna Nie

Yong Weon Yi

Kangdong Liu

Yeon-Sun Seong

Zigang Dong

Dong Joon Kim

Affiliations

Soon will be listed here.

Abstract

Background: Oxidative stress induced growth inhibitor 1 (OSGIN1) regulates cell death. The role and underlying molecular mechanism of OSGIN1 in non-small cell lung cancer (NSCLC) are uncharacterized.

Methods: OSGIN1 expression in NSCLC samples was detected using immunohistochemistry and Western blotting. Growth of NSCLC cells and gefitinib-resistant cells expressing OSGIN1 or TUBB3 knockdown was determined by MTT, soft agar, and foci formation assays. The effect of OSGIN1 knockdown on in vivo tumor growth was assessed using NSCLC patient-derived xenograft models and gefitinib-resistant patient-derived xenograft models. Potentially interacting protein partners of OSGIN1 were identified using IP-MS/MS, immunoprecipitation, PLA, and Western blotting assays. Microtubule dynamics were explored by tubulin polymerization assay and immunofluorescence. Differential expression of signaling molecules in OSGIN1 knockdown cells was investigated using phospho-proteomics, KEGG analysis, and Western blotting.

Results: We found that OSGIN1 is highly expressed in NSCLC tissues and is positively correlated with low survival rates and tumor size in lung cancer patients. OSGIN1 knockdown inhibited NSCLC cell growth and patient-derived NSCLC tumor growth in vivo. Knockdown of OSGIN1 strongly increased tubulin polymerization and re-established gefitinib sensitivity in vitro and in vivo. Additionally, knockdown of TUBB3 strongly inhibited NSCLC cell proliferation. Mechanistically, we found that OSGIN1 enhances DYRK1A-mediated TUBB3 phosphorylation, which is critical for inducing tubulin depolymerization. The results of phospho-proteomics and ontology analysis indicated that knockdown of OSGIN1 led to reduced propagation of the MKK3/6-p38 signaling axis.

Conclusions: We propose that OSGIN1 modulates microtubule dynamics by enhancing DYRK1A-mediated phosphorylation of TUBB3 at serine 172. Moreover, elevated OSGIN1 expression promotes NSCLC tumor growth and gefitinib resistance through the MKK3/6-p38 signaling pathway. Our findings unveil a new mechanism of OSGIN1 and provide a promising therapeutic target for NSCLC treatment in the clinic.

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References

Liu T, Wang Y, Wang J, Ren C, Chen H, Zhang J . DYRK1A inhibitors for disease therapy: Current status and perspectives. Eur J Med Chem. 2021; 229:114062. DOI: 10.1016/j.ejmech.2021.114062. View

Khoi C, Xiao C, Hung K, Lin T, Chiang C . Oxidative Stress-Induced Growth Inhibitor (OSGIN1), a Target of X-Box-Binding Protein 1, Protects Palmitic Acid-Induced Vascular Lipotoxicity through Maintaining Autophagy. Biomedicines. 2022; 10(5). PMC: 9138516. DOI: 10.3390/biomedicines10050992. View

Ko J, Chiu H, Wo T, Huang Y, Tseng S, Huang Y . Inhibition of p38 MAPK-dependent MutS homologue-2 (MSH2) expression by metformin enhances gefitinib-induced cytotoxicity in human squamous lung cancer cells. Lung Cancer. 2013; 82(3):397-406. DOI: 10.1016/j.lungcan.2013.09.011. View

Fourest-Lieuvin A, Peris L, Gache V, Garcia-Saez I, Juillan-Binard C, Lantez V . Microtubule regulation in mitosis: tubulin phosphorylation by the cyclin-dependent kinase Cdk1. Mol Biol Cell. 2005; 17(3):1041-50. PMC: 1382296. DOI: 10.1091/mbc.e05-07-0621. View

Herbst R, Morgensztern D, Boshoff C . The biology and management of non-small cell lung cancer. Nature. 2018; 553(7689):446-454. DOI: 10.1038/nature25183. View

Cheng S, Yang G, Wang W, Leung C, Ma D . The design and development of covalent protein-protein interaction inhibitors for cancer treatment. J Hematol Oncol. 2020; 13(1):26. PMC: 7106679. DOI: 10.1186/s13045-020-00850-0. View

Janke C, Magiera M . The tubulin code and its role in controlling microtubule properties and functions. Nat Rev Mol Cell Biol. 2020; 21(6):307-326. DOI: 10.1038/s41580-020-0214-3. View

Huang J, Lan X, Wang T, Lu H, Cao M, Yan S . Targeting the IL-1β/EHD1/TUBB3 axis overcomes resistance to EGFR-TKI in NSCLC. Oncogene. 2019; 39(8):1739-1755. DOI: 10.1038/s41388-019-1099-5. View

Mariani M, Karki R, Spennato M, Pandya D, He S, Andreoli M . Class III β-tubulin in normal and cancer tissues. Gene. 2015; 563(2):109-14. PMC: 6649683. DOI: 10.1016/j.gene.2015.03.061. View

10.

Dhiman A, Sharma R, Singh R . Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018-2021). Acta Pharm Sin B. 2022; 12(7):3006-3027. PMC: 9293743. DOI: 10.1016/j.apsb.2022.03.021. View

11.

McCarroll J, Gan P, Erlich R, Liu M, Dwarte T, Sagnella S . TUBB3/βIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer. Cancer Res. 2014; 75(2):415-25. DOI: 10.1158/0008-5472.CAN-14-2740. View

12.

Lanczky A, Gyorffy B . Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation. J Med Internet Res. 2021; 23(7):e27633. PMC: 8367126. DOI: 10.2196/27633. View

13.

Greenberg A, Basu S, Hu J, Yie T, Rom W, Lee T . Selective p38 activation in human non-small cell lung cancer. Am J Respir Cell Mol Biol. 2002; 26(5):558-64. DOI: 10.1165/ajrcmb.26.5.4689. View

14.

cermak V, Dostal V, Jelinek M, Libusova L, Kovar J, Rosel D . Microtubule-targeting agents and their impact on cancer treatment. Eur J Cell Biol. 2020; 99(4):151075. DOI: 10.1016/j.ejcb.2020.151075. View

15.

Campbell R, Anderson B, Brooks N, Brooks H, Chan E, de Dios A . Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol Cancer Ther. 2013; 13(2):364-74. DOI: 10.1158/1535-7163.MCT-13-0513. View

16.

Klaunig J . Oxidative Stress and Cancer. Curr Pharm Des. 2019; 24(40):4771-4778. DOI: 10.2174/1381612825666190215121712. View

17.

Kanehisa M, Sato Y, Kawashima M . KEGG mapping tools for uncovering hidden features in biological data. Protein Sci. 2021; 31(1):47-53. PMC: 8740838. DOI: 10.1002/pro.4172. View

18.

Tung C, Chiu H, Jian Y, Jian Y, Chen C, Syu J . Down-regulation of MSH2 expression by an Hsp90 inhibitor enhances pemetrexed-induced cytotoxicity in human non-small-cell lung cancer cells. Exp Cell Res. 2014; 322(2):345-54. DOI: 10.1016/j.yexcr.2014.02.002. View

19.

Yan Y, Tao H, He J, Huang S . The HDOCK server for integrated protein-protein docking. Nat Protoc. 2020; 15(5):1829-1852. DOI: 10.1038/s41596-020-0312-x. View

20.

Kanakkanthara A, Miller J . βIII-tubulin overexpression in cancer: Causes, consequences, and potential therapies. Biochim Biophys Acta Rev Cancer. 2021; 1876(2):188607. DOI: 10.1016/j.bbcan.2021.188607. View