Calpain 2 knockdown promotes cell apoptosis and restores gefitinib sensitivity through epidermal growth factor receptor/protein kinase�B/survivin signaling

Abstract

Gefitinib, an epidermal growth factor receptor (EGFR)-specific drug, is effective for ~1 year, after which resistance is inevitable. Calpain 2 (CAPN2) is known to serve a role in the drug response and resistance in certain cancer therapies. However, the full function of CAPN2, particularly in non-small cell lung cancer, has not yet been elucidated. In the present study, CAPN2 expression in gefitinib-resistant lung adenocarcinoma cells was investigated. CAPN2 function in these cells was further evaluated using gene knockdown both in vitro and in vivo. The results demonstrated that CAPN2 was strongly associated with gefitinib-resistance, and CAPN2 mRNA and protein expression levels were significantly increased in gefitinib-resistant cell lines. Furthermore, CAPN2 knockdown inhibited gefitinib-resistant cell proliferation in vitro and in vivo. CAPN2 conferred gefitinib-resistance by inhibiting cell apoptosis and arresting the cell cycle. CAPN2 knockdown also induced caspase activation and mitochondrial dysfunction, and its function in gefitinib resistance appeared to be largely mediated by EGFR/protein kinase B/survivin signaling pathway activation. These results suggest that CAPN2 is responsible for EGFR-tyrosine kinase inhibitor resistance, and CAPN2 inhibition may be used to provide therapeutic benefits in the treatment of gefitinib resistance.

Near-Infrared Fluorescence Tumor-Targeted Imaging in Lung Cancer: A Systematic Review

“…Another enzyme that is used to activate probes is calpain 2 (CAPN2). This is a protease activated by calcium and has a role in cell proliferation, cell migration, angiogenesis, and tumorigenesis [ 107 ]. The enzyme-activatable peptide probe HSA-CAPN2 was developed by conjugating a CAPN2 peptide sensor to human serum albumin (HSA), which serves as a carrier [ 54 ].…”

Calpain2 Upregulation Regulates EMT-Mediated Pancreatic Cancer Metastasis via the Wnt/β-Catenin Signaling Pathway

“…For instance, depletion of CAPN2 inhibits cell metastasis and proliferation in renal cell carcinoma ( 20 ). Another study demonstrated impaired invasion and metastasis of CAPN2 downregulation in non-small cell lung cancer (NSCLC) ( 33 ). SiRNA-mediated downregulation of CAPN2 expression significantly suppressed adhesion, migration, and invasion in HCC cells ( 15 ).…”

Genetic Variants in Histone Modification Regions Are Associated With the Prognosis of Lung Adenocarcinoma

“…Only a few studies have addressed the role of CAPNs in lung cancer. It has been reported that CAPN2 might promote lung cancer progression by activating EGFR/pAKT signaling pathway, and also contribute to the resistance to paclitaxel or EGFR-TKI (21,22). Another study suggested that overexpression of CAPN4 was an independent prognostic factor in patients with NSCLC, and could enhance the invasive potential of lung cancer cells by upregulating the expression of matrix metalloproteinase 2 (23).…”