RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse
Jaebeom Cho, … , Mien-Chie Hung, Ho-Young Lee
Jaebeom Cho, … , Mien-Chie Hung, Ho-Young Lee
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e136779. https://doi.org/10.1172/JCI136779.
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Research Article Cell biology Oncology

RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse

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.

Authors

Jaebeom Cho, Hye-Young Min, Ho Jin Lee, Seung Yeob Hyun, Jeong Yeon Sim, Myungkyung Noh, Su Jung Hwang, Shin-Hyung Park, Hye-Jin Boo, Hyo-Jong Lee, Sungyoul Hong, Rang-Woon Park, Young Kee Shin, Mien-Chie Hung, Ho-Young Lee

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Figure 2

Identification of RGS2 as a potentially novel biomarker associated with quiescence-like phenotypes and the association of RGS2 expression with poor clinical outcomes.

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Identification of RGS2 as a potentially novel biomarker associated with ...
(A) Venn diagrams of differentially regulated genes in CFSEhi cells compared with CFSElo cells. (B) Gene Ontology (GO) terms significantly enriched in CFSEhi cells compared with CFSElo cells. (C) Upregulated RGS2 mRNA expression in the CFSEhi populations. (D) Kaplan-Meier survival curve showing poor overall and disease-free survival in RGS2hi lung ADC (n = 42) compared with RGS2lo lung ADC (n = 42) in a data set GSE30219. ADC: adenocarcinoma. (E) The correlation between RGS2 expression and cell proliferation–associated gene expressions in NSCLC tumors using a data set GSE63074. (F) GSEA to determine the enrichment of cell proliferation–, stress response-, or UPR-related gene sets in RGS2hi NSCLC using data set GSE3141. NES: normalized enrichment score. (G) Correlation analysis between RGS2 and Ki67 expression in a tissue microarray comprising 40 NSCLC tumors. Scale bar: 100 μm. Scale bar (inset): 50 μm. The data are presented as the mean ± SD. n = 3 for C. **P < 0.01, and ***P < 0.001, as determined by 2-tailed Student’s t test (C) and log-rank test (D). Correlation was determined using Pearson’s and Spearman’s correlation (E and G).