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 Article has an altmetric score of 7

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 5

Reduction in ER stress–induced UPR and ATF4-mediated apoptosis in SCCs.

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Reduction in ER stress–induced UPR and ATF4-mediated apoptosis in SCCs. ...
(A) RNA expression of markers of the 3 UPR branches in SCCs by comparison with their corresponding ACCs was determined by real-time PCR. (B) Immunoblots showing changes in protein expression levels of PERK pathway components in SCCs compared with ACCs. (C) Decreased UPR induction by treatment with thapsigargin (TG; 25 nM) for the indicated time intervals in SCCs compared with ACCs was shown by immunoblotting. (D) Decreased ATF4 target gene induction by paclitaxel treatment (Pc; 20 nM, up to 24 hours) in H460/PcR cells compared with H460 cells was determined by real-time PCR. (E–H) Restoration of protein translation and subsequent cell death resulting from the overexpression of ATF4. Changes in CAP-dependent and -independent protein translation (E), nascent protein synthesis (F), cell proliferation (G) and apoptosis (H) were determined in H460/PcR cells transfected with increasing amounts of ATF4. (I and J) Attenuation of ATF4 overexpression–induced apoptosis by treatment with rapamycin (Rapa; 50 nM, for 12 hours) (I) and with the indicated concentrations of NAC for 24 hours (J). The data are presented as the mean ± SD. n = 3 for A; n = 3 for D; n = 4 or 6 for E; n = 6 for F; n = 3 for G. *P < 0.05, **P < 0.01, and ***P < 0.001, as determined by a 2-tailed Student’s t test (A and D) and 1-way ANOVA with Dunnett’s post hoc test (E-G).