Comparative Proteomics Analysis Reveals the Reversal Effect of Cryptotanshinone on Gefitinib-Resistant Cells in Epidermal Growth Factor Receptor-Mutant Lung Cancer.

Peiheng Cai,Jing Jin,Daifei Wang,Zhongxiang Zhao,Shiqin Jiang,Min Huang,Gaofan Sheng

doi:10.3389/fphar.2022.837055

Peiheng Cai, Jing Jin + Show 5 more

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https://doi.org/10.3389/fphar.2022.837055

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Abstract

Cryptotanshinone (CTS) is a lipophilic constituent of Salvia miltiorrhiza, with a broad-spectrum anticancer activity. We have observed that CTS enhances the efficacy of gefitinib in human lung cancer H1975 cells, yet little is known about its molecular mechanism. To explore how CTS enhances H1975 cell sensitivity to gefitinib, we figured out differential proteins of H1975 cells treated by gefitinib alone or in combination with CTS using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) bioinformatic analyses of the differential proteins were performed. CTS enhanced H1975 cell sensitivity to gefitinib in vitro and in vivo, with 115 and 128 differential proteins identified, respectively. GO enrichment, KEGG analysis, and PPI network comprehensively demonstrated that CTS mainly impacted the redox process and fatty acid metabolism in H1975 cells. Moreover, three differential proteins, namely, catalase (CAT), heme oxygenase 1 (HMOX1), and stearoyl-CoA desaturase (SCD) were validated by RT-qPCR and Western blot. In conclusion, we used a proteomic method to study the mechanism of CTS enhancing gefitinib sensitivity in H1975 cells. Our finding reveals the potential protein targets of CTS in overcoming gefitinib resistance, which may be therapeutical targets in lung cancer.

Highlights

Lung cancer is one of the most malignant tumors, with high morbidity and mortality over the world
To investigate the effect of cryptotanshinone (CTS) on chemosensitivity of human lung cancer, the gefitinibresistant H1975 cells were treated with different concentrations of gefitinib alone or together with CTS
We discovered that CTS enhances the sensitivity of H1975 cells to gefitinib

Summary

Introduction

Lung cancer is one of the most malignant tumors, with high morbidity and mortality over the world. About 80% of lung cancers are non-small cell lung cancers (NSCLCs), and epidermal growth factor receptor (EGFR) gene mutations are considered to prompt NSCLC development (Sharma et al, 2007). EGFR-tyrosine kinase inhibitors (TKIs) have shown good clinical efficacy, therapy resistance inevitably occurs. With long-term use of first-line EGFR-TKIs, most patients would develop acquired resistance after a median of 12 months (Nagano et al, 2018). Mechanisms of Proteomics in Cryptotanshinone Reversing Chemoresistance resistance to EGFR-TKIs are complicated, including T790M secondary mutation, activation of alternative or downstream pathways, histological transformation, etc., (Yu et al, 2014). Overcoming the resistance to EGFR-TKIs has become a hotspot of research

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