한빛사 논문
Jaebeom Cho,1 Hye-Young Min,1,2 Ho Jin Lee,1 Seung Yeob Hyun,1 Jeong Yeon Sim,1,3 Myungkyung Noh,1 Su Jung Hwang,4 Shin-Hyung Park,2 Hye-Jin Boo,1,2 Hyo-Jong Lee,4 Sungyoul Hong,2 Rang-Woon Park,5 Young Kee Shin,2,3 Mien-Chie Hung,6,7 and Ho-Young Lee1,2,*
1Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, 2College of Pharmacy and Research Institute of Pharmaceutical Sciences, and 3Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, Republic of Korea. 4College of Pharmacy, Inje University, Gimhae, Gyungnam, Republic of Korea. 5Department of Biochemistry and Cell Biology, School of Medicine, and Cell & Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea. 6Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. 7Department of Biotechnology, Asia University, Taichung, Taiwan.
*Address correspondence to: Ho-Young Lee, Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
Abstract
Slow-cycling/dormant cancer cells (SCCs) have pivotal roles in driving cancer relapse and drug resistance. A mechanistic explanation for cancer cell dormancy and therapeutic strategies targeting SCCs are necessary to improve patient prognosis, but are limited because of technical challenges to obtaining SCCs. Here, by applying proliferation-sensitive dyes and chemotherapeutics to non–small cell lung cancer (NSCLC) cell lines and patient-derived xenografts, we identified a distinct SCC subpopulation that resembled SCCs in patient tumors. These SCCs displayed major dormancy-like phenotypes and high survival capacity under hostile microenvironments through transcriptional upregulation of regulator of G protein signaling 2 (RGS2). Database analysis revealed RGS2 as a biomarker of retarded proliferation and poor prognosis in NSCLC. We showed that RGS2 caused prolonged translational arrest in SCCs through persistent eukaryotic initiation factor 2 (eIF2α) phosphorylation via proteasome-mediated degradation of activating transcription factor 4 (ATF4). Translational activation through RGS2 antagonism or the use of phosphodiesterase 5 inhibitors, including sildenafil (Viagra), promoted ER stress–induced apoptosis in SCCs in vitro and in vivo under stressed conditions, such as those induced by chemotherapy. Our results suggest that a low-dose chemotherapy and translation-instigating pharmacological intervention in combination is an effective strategy to prevent tumor progression in NSCLC patients after rigorous chemotherapy.
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