Knockdown of CABYR-a/b increases chemosensitivity of human non-small cell lung cancer cells through inactivation of Akt

• Published in: Molecular cancer research Vol. 12; no. 3; pp. 335 - 347
• Main Authors: Qian, Zunlei, Li, Min, Wang, Rui, Xiao, Qianqian, Wang, Jing, Li, Mingying, He, Dacheng, Xiao, Xueyuan
• Format: Journal Article
• Language: English
• Published: United States 01.03.2014
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Calcium-Binding Proteins - antagonists & inhibitors; Calcium-Binding Proteins - deficiency; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Cisplatin - pharmacology; Disease Progression; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mice, Inbred BALB C; Mice, Nude; Paclitaxel - pharmacology; Phosphoproteins - antagonists & inhibitors; Phosphoproteins - deficiency; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein Isoforms; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Transfection; Xenograft Model Antitumor Assays
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-13-0391

CABYR is a calcium-binding tyrosine phosphorylation-regulated protein that was identified as a novel cancer testis antigen in lung cancer in our previous study. However, the role of CABYR as a driver of disease progression or as a chemosensitizer is poorly understood. This study sought to investigate the relationship between the expression levels of CABYR-a/b, which are the two predominant isoforms of the five isoform proteins encoded by CABYR, and chemosensitivity in non-small cell lung cancer cells. We found that the short hairpin RNA-mediated knockdown of CABYR-a/b significantly inhibited the proliferation of NCI-H460 and A549 cells and resulted in the attenuation of Akt phosphorylation, which is constitutively active in lung cancer cells. The silencing of CABYR-a/b expression notably impacted the downstream components of the Akt pathways: decreasing the phospho-GSK-3β (Ser9) levels and increasing the expression of the p53 and p27 proteins. Furthermore, CABYR-a/b knockdown led to a significant increase in chemosensitivity in response to chemotherapeutic drugs and drug-induced apoptosis, both in vitro and in vivo. Conversely, the transient transfection of CABYR-a/b-depleted cells with constitutively active Akt partially restored the resistance to cisplatin and paclitaxel and significantly decreased the activation of GSK-3β and cleaved PARP. Taken together, our results suggest that the inhibition of CABYR-a/b is a novel method to improve the apoptotic response and chemosensitivity in lung cancer and that this cancer testis antigen is an attractive target for lung cancer drug development. Suppression of CABYR-a/b expression increases chemosensitivity of lung cancer cells by inhibiting Akt activity.