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 9

Chemotherapeutic sensitization via the deregulation of translational control in SCCs.

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Chemotherapeutic sensitization via the deregulation of translational con...
(A) Immunoblotting of markers related to cell proliferation, growth, and survival in PDE5 inhibitor–treated H460/PcR cells. (B–D) Cell viability (B), anchorage-dependent colony formation (C), and apoptosis (D) in H460/PcR cells treated with either PDE5 inhibitor alone or in combination with paclitaxel (Pc; 20 nM). (E and F) Abrogation of sildenafil-mediated enhancement of Pc-induced apoptosis in H460/PcR cells by treatment with rapamycin (Rapa; 50 nM) (E) or NAC (10 mM) (F) in combination. (G–I) Potentiation of tumor growth inhibition by combined treatment with chemotherapy and sildenafil (Sild) in NOD/SCID mice bearing SCC (H460/PcR and H1299/CsR) xenografts (G) and PDX (H) (H460/PcR, Con (control): n = 6, Sild: n = 6, Pc: n = 8, Sild+Pc: n = 8; H1299/CsR, Con: n = 5, Sild: n = 5, cisplatin [Cs]: n = 5, Sild+Cs: n = 6; PDX1, n = 6 per group). (I) IHC analyses for Cl-Cas3 in tumors treated with a combination of chemotherapy and sildenafil. The data are presented as the mean ± SD. n = 4 for B; n = 3 for C; n = 6–18 for I. *P < 0.05, **P < 0.01, and ***P < 0.001, as determined by 1-way ANOVA with Dunnett’s post hoc test.