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GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma

Oncogene (2024)Cite this article

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Abstract

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.

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Fig. 1: GSTO1 contributes to EGFR-TKIs resistance and cell migration in lung adenocarcinoma cells.
Fig. 2: GSTO1-NPM1 interaction promotes erlotinib resistance and cell migration in an AKT/NF-κB-dependent manner.
Fig. 3: GSTO1 enzyme activity is essential for NPM1 deglutathionylation.
Fig. 4: GSTO1 promotes metastasis and erlotinib resistance in mouse xenograft models of lung adenocarcinoma.
Fig. 5: GSTO1 facilitates tumor growth and osimeritinib resistance via its enzyme activity in lung adenocarcinoma.
Fig. 6: High level of GSTO1 is positively correlated with cancer progression of human lung adenocarcinoma.

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Data availability

GSTO1 level analysis, correlation analysis and Kaplan–Meier analysis were conducted with a LUAD cohort composed of 51 individuals from GSE140343 dataset (https://www.ncbi.nlm.nih.gov/geo/) [34] and a 181-individual cohort from GSE50081 dataset derived from LUNG CANCER EXPLORER (https://lce.biohpc.swmed.edu/lungcancer/) [35, 60]. The gene sets for GSEA were downloaded from MSigDB databases (http://www.gsea-msigdb.org/gsea/downloads.jsp). GO and KEGG analysis was performed with the DAVID (Version 6.8) bioinformatics Database [61, 62] (https://david.ncifcrf.gov/). Graphical abstract was created with BioRender.com. The shRNA screening, RNA-Seq and mass spectrometry data from this publication would be deposited to the Mendeley Data (https://data.mendeley.com/datasets/xjrj4zgc34/1).

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Acknowledgements

We are grateful for the grants from the National Natural Science Foundation of China (82073868), Science and Technology Commission of Shanghai Municipality (20S11900100), China Postdoctoral Science Foundation (2022M722138), the Fundamental Research Funds for the Central Universities. Prof. Jie Yang kindly provided technical assistance with construction of NPM1 C/S mutant plasmids. Our proteomics and mass spectrometry work were performed at the Proteomics Platform of Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine.

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  1. These authors contributed equally: Ning-xiang Shen, Ming-yu Luo, Wei-ming Gu.

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Ning-xiang Shen, Ming-yu Luo, Wei-ming Gu, Miaomiao Gong, Hui-min Lei, Cheng Wang, Mo-cong Zhang, Lu Xu, Liang Zhu & Ying Shen

  2. Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China

    Ning-xiang Shen, Ming-yu Luo, Wei-ming Gu, Miaomiao Gong, Hui-min Lei, Cheng Wang, Mo-cong Zhang, Lu Xu, Liang Zhu & Ying Shen

  3. Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Ling Bi

  4. State Key Laboratory of Oncogenes and Related Genes, Department of Thoracic Surgery, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Guanglei Zhuang

  5. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Hong-zhuan Chen

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Contributions

YS conceived and supervised the project. N-XS, M-YL, W-MG, M-MG, H-ML, LB, CW, M-CZ, and LX designed and conducted the experiments. G-LZ provided some essential materials, such as established EGFR-TKIs-resistant cells and plasmids. YS, LZ, and H-ZC edited the manuscript with inputs from N-XS, M-YL, and W-MG All the authors reviewed and approved the final manuscript.

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Shen, Nx., Luo, My., Gu, Wm. et al. GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma. Oncogene (2024). https://doi.org/10.1038/s41388-024-03096-z

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