KIRAMS / 김태우, 홍성희*
Abstract
Background: Peroxisome proliferator-activated receptor γ (PPARγ) agonists frequently induce cell death in human non-small-cell lung cancer (NSCLC) cells. However, majority of NSCLC patients acquire resistance after cancer therapy, and it is still unclear.
Methods: In this study we investigated the apoptotic mechanism and the anti-cancer effects of a novel purine-based PPARγ agonist, CB11 (8-(2-aminophenyl)-3-butyl-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), on human NSCLC cells. CB11 mediates PPARγ-dependent cell death, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) collapse, cell cycle arrest, lactate dehydrogenase (LDH) cytotoxicity, and caspase-3 activity in human NSCLC cells.
Results: CB11 causes cell death via ROS-mediated ATM-p53-GADD45α signalling in human NSCLC cells, and diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, decreases cell death by inhibiting CB11-mediated ATM signalling. In a xenograft experiment, CB11 dramatically reduced tumour volume when compared to a control group. Furthermore, CB11 induced cell death by inhibiting epithelial-to-mesenchymal transition (EMT) under radiation exposure in radiation-resistant human NSCLC cells. However, PPARγ deficiency inhibited cell death by blocking the ATM-p53 axis in radiation/CB11-induced radiation-resistant human NSCLC cells.
Conclusions: Taken together, our results suggest that CB11, a novel PPARγ agonist, may be a novel anti-cancer agent, and it could be useful in a therapeutic strategy to overcome radio-resistance in radiation-exposed NSCLC.
Affiliations
Tae Woo Kim 1 , Da-Won Hong 2 , Joung Whan Park 1 , Sung Hee Hong 3
1 Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Republic of Korea.
2 Laboratory of RNA Cell Biology, Graduate Department of Bioconvergence Science and Technology, Dankook University, Jukjeon-ro 152, Suji-gu, Yongin-si, Gyeonggi-do, 16892, Republic of Korea.
3 Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, 139-706, Republic of Korea. gobrian@kcch.re.kr.