Antitumor Effect of Calcium-Mediated Destabilization of Epithelial Growth Factor Receptor on Non-Small Cell Lung Carcinoma
- Authors
- Kim, In Un; Sung, In Sung; Sim, Jae Jun; Park, Minhee; Jeong, Keun-Yeong; Kim, Hwan Mook
- Issue Date
- Apr-2018
- Publisher
- MDPI
- Keywords
- non-small-cell lung carcinoma; epithelial growth factor receptor; Src; alpha-tubulin; calcium; calpain
- Citation
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.19, no.4
- Journal Title
- INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
- Volume
- 19
- Number
- 4
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/3918
- DOI
- 10.3390/ijms19041158
- ISSN
- 1422-0067
- Abstract
- Despite the development of numerous therapeutics targeting the epithelial growth factor receptor (EGFR) for non-small cell lung carcinoma (NSCLC), the application of these drugs is limited because of drug resistance. Here, we investigated the antitumor effect of calcium-mediated degradation of EGFR pathway-associated proteins on NSCLC. First, lactate calcium salt (LCS) was utilized for calcium supplementation. Src, alpha-tubulin and EGFR levels were measured after LSC treatment, and the proteins were visualized by immunocytochemistry. Calpeptin was used to confirm the calcium-mediated effect of LCS on NSCLC. Nuclear expression of c-Myc and cyclin D1 was determined to understand the underlying mechanism of signal inhibition following EGFR and Src destabilization. The colony formation assay and a xenograft animal model were used to confirm the in vitro and in vivo antitumor effects, respectively. LCS supplementation reduced Src and alpha-tubulin expression in NSCLC cells. EGFR was destabilized because of proteolysis of Src and alpha-tubulin. c-Myc and cyclin D1 expression levels were also reduced following the decrease in the transcriptional co-activation of EGFR and Src. Clonogenic ability and tumor growth were significantly inhibited by LSC treatment-induced EGFR destabilization. These results suggest that other than specifically targeting EGFR, proteolysis of associated molecules such as Src or alpha-tubulin may effectively exert an antitumor effect on NSCLC via EGFR destabilization. Therefore, LCS is expected to be a good candidate for developing novel anti-NSCLC therapeutics overcoming chemoresistance.
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