title: Knockdown of CABYR-a/b increases chemosensitivity of human non-small cell lung cancer cells through inactivation of Akt.
abstract: 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.
  
  
  CONCLUSIONS
  Suppression of CABYR-a/b expression increases chemosensitivity of lung cancer cells by inhibiting Akt activity.
authors.affiliation: Key Laboratory of Cell Proliferation and Regulation of the Ministry of Education, Beijing Normal University, 19th Xinjiekouwai St. 100875, Beijing, China. xyxiao@bnu.edu.cn.
authors.forename: Zunlei
authors.initials: Z
authors.lastname: Qian
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Xiao
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Mingying
authors.initials: M
authors.lastname: Li
authors.forename: Dacheng
authors.initials: D
authors.lastname: He
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C448922:CABYR protein, human; D002135:Calcium-Binding Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel; D002945:Cisplatin