CPNE1 promotes non-small cell lung cancer progression by interacting with RACK1 via the MET signaling pathway

Background: Non-small cell lung Cancer (NSCLC) is the most common type of lung Cancer and the most lethal tumour worldwide. Copine 1 (CPNE1) was identified as a novel oncogene in NSCLC in our previous study. However, its specific function and relative mechanisms remain poorly understood.

Methods: The biological role of CPNE1 and RACK1 in NSCLC was investigated using gene expression knockdown and overexpression, cell proliferation assays, clonogenic assays, and Transwell assays. The expression levels of CPNE1, RACK1 and other proteins were determined by western blot analysis. The relationship between CPNE1 and RACK1 was predicted and investigated by mass spectrometry analysis, immunofluorescence staining, and coimmunoprecipitation. NSCLC cells were treated with a combination of a Met Inhibitor and gefitinib in vitro and in vivo.

Results: We found that CPNE1 facilitates tumorigenesis in NSCLC by interacting with RACK1, which further induces activation of MET signaling. CPNE1 overexpression promoted cell proliferation, migration, invasion and MET signaling in NSCLC cells, whereas CPNE1 knockdown produced the opposite effects. In addition, the suppression of the enhancing effect of CPNE1 overexpression on tumorigenesis and MET signaling by knockdown of RACK1 was verified. Moreover, compared to single-agent treatment, dual blockade of MET and EGFR resulted in enhanced reductions in the tumour volume and downstream signaling in vivo.

Conclusions: Our findings show that CPNE1 promotes tumorigenesis by interacting with RACK1 and activating MET signaling. The combination of a Met Inhibitor with an EGFR-TKI attenuated tumour growth more significantly than either single-drug treatment. These findings may provide new insights into the biological function of CPNE1 and the development of novel therapeutic strategies for NSCLC. Video Abstract.

Copine 1 (CPNE1); Epidermal growth factor receptor (EGFR); Mesenchymal-epithelial transition tyrosine kinase receptor (MET); Non-small cell lung cancer (NSCLC); Receptor for activated C kinase 1 (RACK1).