title: The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes.
abstract: Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Xing
authors.affiliation: State Key Lab of Ophthalmology, Guangdong Provincial Key Lab of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 500040, China; School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Yizhao
authors.initials: Y
authors.lastname: Luan
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Sihan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jialuo
authors.initials: J
authors.lastname: Mai
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jiankai
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Longxiang
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Bingzheng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Mingshi
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Pengxin
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Xingwen
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Sai
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
authors.forename: Furong
authors.initials: F
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: BGI-Shenzhen, Shenzhen 518031, China.
authors.forename: Shida
authors.initials: S
authors.lastname: Zhu
authors.affiliation: BGI-Shenzhen, Shenzhen 518031, China.
authors.forename: Dongbing
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Neurology and Northwestern Brain Tumor Institute, Center for Genetic Medicine, H. Robert Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Shiyuan
authors.initials: S
authors.lastname: Cheng
authors.affiliation: State Key Lab of Ophthalmology, Guangdong Provincial Key Lab of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 500040, China. Electronic address: xiezhi@gmail.com.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: zhuwenbo@mail.sysu.edu.cn.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: ygm@mail.sysu.edu.cn.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D001678:Organelle Biogenesis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005904:Glial Fibrillary Acidic Protein; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP
keywords: PGC1α; PPARγ coactivator-1α; Warburg effect; cAMP; cyclic adenosine monophosphate; glioblastoma; glycolysis; induced differentiation; metabolic reprogramming; mitochondrial biogenesis; oxidative phosphorylation