title: Anti-neoplastic activity of low-dose endothelial-monocyte activating polypeptide-II results from defective autophagy and G2/M arrest mediated by PI3K/Akt/FoxO1 axis in human glioblastoma stem cells.
abstract: Glioblastoma multiforme (GBM) is a life-threatening brain tumor with fatal recurrence, for which glioblastoma stem cells (GSCs) are held responsible. Though endothelial-monocyte activating polypeptide-II (EMAP-II) has been confirmed as a possible antitumor agent that can induce apoptosis of endothelial cells and inhibit tumor angiogenesis, the direct cytotoxicity by EMAP-II on tumor cells and its underlying mechanism are largely unknown. In the present study, it was demonstrated that low-dose (0.05 nM) EMAP-II reduces cell viability and mitochondrial membrane potential in vitro. Likewise, EMAP-II suppressed tumor growth in GSC-xenografted mice. Though no apoptosis was detected, all these antitumor effects were attenuated when GSCs were pretreated with 3-methyladenine (3-MA). Analysis of EMAP-II-treated GSCs exhibited the morphological and biochemical changes typical of autophagy, which was further shown to be defective. Moreover, EMAP-II was found to suppress tumor growth by inducing G2/M arrest in GSCs. Our data further showed that EMAP-II inhibited PI3K/Akt activation with concomitant induction of FoxO1 activation. FoxO1 knockdown significantly attenuated the induction of autophagy and G2/M arrest. Excessive accumulation of lipid droplets was intriguingly detected by transmission electron microscope, which was accompanied by autophagosomes. Further investigation indicated that the transcriptional regulation of Atg2B by FoxO1 was responsible for the induction of autophagy and formation of lipid droplets. These results suggest that EMAP-II is an effective anticancer agent for glioblastoma therapy, which can induce direct growth suppression in GSCs through defective autophagy and G2/M arrest mediated by the PI3K/Akt/FoxO1 axis.
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Libo
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Yixue
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Fanjie
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China. Electronic address: liuyunhui2014@yeah.net.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000648:ultrastructure; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015290:Second Messenger Systems / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C077219:small inducible cytokine subfamily E, member 1; D058539:Phosphatidylinositol 3-Kinase
keywords: 3-Methyladenine (PubChem CID: 1673); Atg2B; Autophagy; EMAP-II; FoxO1; GSCs; Insulin-like growth factor-1 (PubChem CID: 44134783)