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Int. J. Mol. Sci. 2018, 19(4), 1158; https://doi.org/10.3390/ijms19041158

Antitumor Effect of Calcium-Mediated Destabilization of Epithelial Growth Factor Receptor on Non-Small Cell Lung Carcinoma

1
Gachon Institute of Pharmaceutical Science, Gachon University, 191, Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Korea
2
Metimedi Pharmaceuticals Co. R&D Division, 263, Central-ro, Yeonsu-Gu, Incheon 22006, Korea
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 17 January 2018 / Revised: 3 April 2018 / Accepted: 3 April 2018 / Published: 11 April 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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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, α-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 α-tubulin expression in NSCLC cells. EGFR was destabilized because of proteolysis of Src and α-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 α-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. View Full-Text
Keywords: non-small-cell lung carcinoma; epithelial growth factor receptor; Src; alpha-tubulin; calcium; calpain non-small-cell lung carcinoma; epithelial growth factor receptor; Src; alpha-tubulin; calcium; calpain
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kim, I.U.; Sung, I.S.; Sim, J.J.; Park, M.; Jeong, K.-Y.; Kim, H.M. Antitumor Effect of Calcium-Mediated Destabilization of Epithelial Growth Factor Receptor on Non-Small Cell Lung Carcinoma. Int. J. Mol. Sci. 2018, 19, 1158.

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