1. RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse
- Author
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Su Jung Hwang, Hye-Young Min, Rang Woon Park, Jaebeom Cho, Ho-Young Lee, Mien Chie Hung, Hyo Jong Lee, Ho Jin Lee, Jeong Yeon Sim, Myungkyung Noh, Shin-Hyung Park, Seung Yeob Hyun, Hye-Jin Boo, Sungyoul Hong, and Young Kee Shin
- Subjects
0301 basic medicine ,Lung Neoplasms ,medicine.medical_treatment ,Mice, SCID ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Mice, Inbred NOD ,Recurrence ,Carcinoma, Non-Small-Cell Lung ,medicine ,Animals ,Humans ,Lung cancer ,neoplasms ,Chemotherapy ,business.industry ,ATF4 ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,Neoplasm Proteins ,stomatognathic diseases ,030104 developmental biology ,Tumor progression ,Apoptosis ,030220 oncology & carcinogenesis ,Protein Biosynthesis ,Cancer cell ,Cancer research ,Biomarker (medicine) ,Female ,business ,RGS Proteins ,Research Article - 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.
- Published
- 2023