Inhibiting DX2-p14/ARF Interaction Exerts Antitumor Effects in Lung Cancer and Delays Tumor Progression.
The aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) splice variant designated DX2 is induced by cigarette smoke carcinogens and is often detected in human lung cancer specimens. However, the function of DX2 in lung carcinogenesis is obscure. In this study, we found that DX2 expression was induced by oncogenes in human lung cancer tissues and cells. DX2 prevented oncogene-induced apoptosis and senescence and promoted drug resistance by directly binding to and inhibiting p14/ARF. Through chemical screening, we identified SLCB050, a novel compound that blocks the interaction between DX2 and p14/ARF in vitro and in vivo SLCB050 reduced the viability of human lung cancer cells, especially small cell lung cancer cells, in a p14/ARF-dependent manner. Moreover, in a mouse model of K-Ras-driven lung tumorigenesis, ectopic expression of DX2 induced small cell and non-small cell lung cancers, both of which could be suppressed by SLCB050 treatment. Taken together, our findings show how DX2 promotes lung cancer progression and how its activity may be thwarted as a strategy to treat patients with lung cancers exhibiting elevated DX2 levels. Cancer Res; 76(16); 4791-804. ©2016 AACR.
Department of Molecular Biology, Pusan National University, Busan, Republic of Korea (South).
Ah-Young
AY
Oh
Department of Molecular Biology, Pusan National University, Busan, Republic of Korea (South).
Youn Sang
YS
Jung
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea (South).
Jiseon
J
Kim
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea (South).
Jee-Hyun
JH
Lee
Department of Molecular Biology, Pusan National University, Busan, Republic of Korea (South).
Jung-Hyun
JH
Cho
Department of Molecular Biology, Pusan National University, Busan, Republic of Korea (South).
Ho-Young
HY
Chun
Department of Molecular Biology, Pusan National University, Busan, Republic of Korea (South).
Soyoung
S
Park
Forensic DNA Division, National Forensic Service, Wonju, Republic of Korea (South).
Hyunchul
H
Park
Forensic DNA Division, National Forensic Service, Wonju, Republic of Korea (South).
Sikeun
S
Lim
Program in Food Science and Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea (South).
Nam-Chul
NC
Ha
Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Gyeonggi Do, Republic of Korea (South).
Jong Sook
JS
Park
Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Gyeonggi Do, Republic of Korea (South).
Choon-Sik
CS
Park
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea (South). bjpark1219@pusan.ac.kr gysong@cnu.ac.kr.
Gyu-Yong
GY
Song
Department of Molecular Biology, Pusan National University, Busan, Republic of Korea (South). bjpark1219@pusan.ac.kr gysong@cnu.ac.kr.
Bum-Joon
BJ
Park
D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000378:metabolism / Q000473:pathology*
C575685:AIMP2 protein, human; C401561:CDK2AP2 protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins