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Regulation of cAMP and GSK3 signaling pathways contributes to the neuronal conversion of glioma.

 Jinsoo Oh  ;  Yongbo Kim  ;  Lihua Che  ;  Jeong Beom Kim  ;  Gyeong Eon Chang  ;  Eunji Cheong  ;  Seok-Gu Kang  ;  Yoon Ha 
 PLOS ONE, Vol.12(11) : e0178881, 2017 
Journal Title
Issue Date
Animals ; Cell Differentiation/drug effects* ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Reprogramming/drug effects* ; Colforsin/administration & dosage ; Cyclic AMP/antagonists & inhibitors ; Cyclic AMP/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/drug therapy* ; Glioma/genetics* ; Glioma/pathology ; Glycogen Synthase Kinase 3/antagonists & inhibitors ; Glycogen Synthase Kinase 3/genetics* ; Humans ; Mice ; Neurons/drug effects ; Neurons/metabolism ; Optical Imaging ; Pyridines/administration & dosage ; Pyrimidines/administration & dosage ; Rats ; Signal Transduction/drug effects ; Small Molecule Libraries/administration & dosage ; Xenograft Model Antitumor Assays
Glioma is the most malignant type of primary central nervous system tumors, and has an extremely poor prognosis. One potential therapeutic approach is to induce the terminal differentiation of glioma through the forced expression of pro-neural factors. Our goal is to show the proof of concept of the neuronal conversion of C6 glioma through the combined action of small molecules. We investigated the various changes in gene expression, cell-specific marker expression, signaling pathways, physiological characteristics, and morphology in glioma after combination treatment with two small molecules (CHIR99021, a glycogen synthase kinase 3 [GSK3] inhibitor and forskolin, a cyclic adenosine monophosphate [cAMP] activator). Here, we show that the combined action of CHIR99021 and forskolin converted malignant glioma into fully differentiated neurons with no malignant characteristics; inhibited the proliferation of malignant glioma; and significantly down-regulated gene ontology and gene expression profiles related to cell division, gliogenesis, and angiogenesis in small molecule-induced neurons. In vivo, the combined action of CHIR99021 and forskolin markedly delayed neurological deficits and significantly reduced the tumor volume. We suggest that reprogramming technology may be a potential treatment strategy replacing the therapeutic paradigm of traditional treatment of malignant glioma, and a combination molecule comprising a GSK3 inhibitor and a cAMP inducer could be the next generation of anticancer drugs.
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1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Ha, Yoon(하윤)
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