Peruvoside is a novel Src inhibitor that suppresses NSCLC cell growth and motility by downregulating multiple Src-EGFR-related pathways

Yihua Lai; Hsiuhui Chang; Hueiwen Chen; Geechen Chang; Jeremy Jw Chen

Peruvoside is a novel Src inhibitor that suppresses NSCLC cell growth and motility by downregulating multiple Src-EGFR-related pathways

Am J Cancer Res. 2022 Jun 15;12(6):2576-2593. eCollection 2022.

Authors

Yihua Lai^{1

2

3

4}, Hsiuhui Chang¹, Hueiwen Chen⁵, Geechen Chang^{6

7}, Jeremy Jw Chen^{1

8

9}

Affiliations

¹ Institute of Biomedical Sciences, National Chung Hsing University Taichung, Taiwan.
² Rheumatic Diseases Research Center, China Medical University Hospital Taichung, Taiwan.
³ College of Medicine, China Medical University Taichung, Taiwan.
⁴ Rheumatology and Immunology Center, China Medical University Hospital Taichung, Taiwan.
⁵ Graduate Institute of Toxicology, National Taiwan University College of Medicine Taipei, Taiwan.
⁶ Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital Taichung, Taiwan.
⁷ School of Medicine, Chung Shan Medical University Taichung, Taiwan.
⁸ Biotechnology Center, National Chung Hsing University Taichung, Taiwan.
⁹ Institute of Molecular Biology, National Chung Hsing University Taichung, Taiwan.

PMID: 35812056
PMCID: PMC9251685

Abstract

The tyrosine kinase Src plays an essential role in the progression of many cancers and is involved in several epidermal growth factor receptor (EGFR)-mediated signalling pathways. To improve the efficacy of lung cancer treatments, this study aimed to identify novel compounds that can disrupt the Src-EGFR interaction and that are less dependent on EGFR status with wild-type and mutations than other compounds. We used the Src pY419 ELISA as the platform to screen a compound library of more than 400 plant-derived active ingredients and identified peruvoside as a candidate Src-EGFR crosstalk inhibitor. The effects of peruvoside were evaluated by western blotting, cell function assays, combination Index (CI)-isobologram analyses and in vivo experiments. Peruvoside significantly suppressed the phosphorylation of Src, EGFR, and signal transducer and activator of transcription 3 (STAT3) in a dose- and time-dependent manner and somewhat suppressed their protein expression. Cell function assays revealed that peruvoside inhibited the proliferation, invasion, migration, and colony formation of lung cancer cells in vitro and tumour growth in vivo. Furthermore, peruvoside sensitized gefitinib-resistant tumour cells (A549, PC9/gef and H1975) to gefitinib treatment, indicating that peruvoside may exert synergistic effects when used in combination with established therapeutic agents. Our data also demonstrated that the inhibitory effects of peruvoside on lung cancer progression might be attributed to its ability to regulate Src, phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinase (JNK), Paxillin, p130cas, and EGFR. Our findings suggest that peruvoside suppresses non-small-cell lung carcinoma (NSCLC) malignancy by downregulating multiple Src-related pathways and could serve as a potential base molecule for developing new anticancer drugs and therapeutic strategies for lung cancer.

Keywords: Src; epidermal growth factor receptor; gefitinib; non-small-cell lung carcinoma; peruvoside.