Title: AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells
Abstract: The FASEB JournalVolume 33, Issue 3 p. 4525-4537 ResearchFree to Read AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells Lijuan Du, Lijuan Du Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaThese authors contributed equally to this work.Search for more papers by this authorFan Yang, Corresponding Author Fan Yang [email protected] Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaThese authors contributed equally to this work. Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected] Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected]Search for more papers by this authorHoushun Fang, Houshun Fang Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorHuiying Sun, Huiying Sun Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorYao Chen, Yao Chen Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorYan Xu, Yan Xu Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorHui Li, Hui Li Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Pharmacology and Chemical Biology, School of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorLiang Zheng, Liang Zheng Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorBin-Bing S. Zhou, Corresponding Author Bin-Bing S. Zhou [email protected] Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Pharmacology and Chemical Biology, School of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected] Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected]Search for more papers by this author Lijuan Du, Lijuan Du Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaThese authors contributed equally to this work.Search for more papers by this authorFan Yang, Corresponding Author Fan Yang [email protected] Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaThese authors contributed equally to this work. Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected] Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected]Search for more papers by this authorHoushun Fang, Houshun Fang Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorHuiying Sun, Huiying Sun Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorYao Chen, Yao Chen Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorYan Xu, Yan Xu Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorHui Li, Hui Li Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Pharmacology and Chemical Biology, School of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorLiang Zheng, Liang Zheng Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSearch for more papers by this authorBin-Bing S. Zhou, Corresponding Author Bin-Bing S. Zhou [email protected] Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Pharmacology and Chemical Biology, School of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected] Correspondence: Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Rd., Shanghai 200127, China. E-mail: [email protected]Search for more papers by this author First published: 31 January 2019 https://doi.org/10.1096/fj.201801559RRCitations: 1 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL ABSTRACT It has been shown that 5-amino-4-imidazolecarboxamide riboside (AICAr) can inhibit cell proliferation and induce apoptosis in childhood acute lymphoblastic leukemia (ALL) cells. Although AICAr could regulate cellular energy metabolism by activating AMPK, the cytotoxic mechanisms of AICAr are still unclear. Here, we knocked out TP53 or PRKAA1 gene (encoding AMPKα1) in NALM-6 and Reh cells by using the clustered regularly interspaced short palindromic repeats/Cas9 system and found that AICAr-induced proliferation inhibition was independent of AMPK activation but dependent on p53. Liquid chromatography–mass spectrometry analysis of nucleotide metabolites indicated that AICAr caused an increase in adenosine triphosphate, deoxyadenosine triphosphate, and deoxyguanosine triphosphate levels by up-regulating purine biosynthesis, while AICAr led to a decrease in cytidine triphosphate, uridine triphosphate, deoxycytidine triphosphate, and deoxythymidine triphosphate levels because of reduced phosphoribosyl pyrophosphate production, which consequently impaired the pyrimidine biosynthesis. Ribonucleoside triphosphate (NTP) pool imbalances suppressed the rRNA transcription efficiency. Furthermore, deoxy-ribonucleoside triphosphate (dNTP) pool imbalances induced DNA replication stress and DNA double-strand breaks, followed by cell cycle arrest and apoptosis in ALL cells. Exogenous uridine could rebalance the NTP and dNTP pools by supplementing pyrimidine and then attenuate AICAr-induced cytotoxicity. Our data indicate that RNA transcription inhibition and DNA replication stress induced by NTP and dNTP pool imbalances might play a key role in AICAr-mediated cytotoxic effects on ALL cells, suggesting a potential clinical application of AICAr in future ALL therapy.—Du, L., Yang, F., Fang, H., Sun, H., Chen, Y., Xu, Y., Li, H., Zheng, L., Zhou, B.-B. S. AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells. FASEB J. 33, 4525–4537 (2019). www.fasebj.org Citing Literature Volume33, Issue3March 2019Pages 4525-4537 RelatedInformation