title: ASK1 regulates the survival of neuroblastoma cells by interacting with TLX and stabilizing HIF-1α.
abstract: Elevated expression of TLX (also called as NR2E1) in neuroblastoma (NB) correlates with unfavorable prognosis, and TLX is required for self-renewal of NB cells. Knockdown of TLX has been shown to reduce the NB sphere-forming ability. ASK1 (MAP3K5) and TLX expression are both enhanced in SP (side population) NB and patient-derived primary NB sphere cell lines, but the majority of non-SP NB lines express lower ASK1 expression. We found that ASK1 phosphorylated and stabilized TLX, which led induction of HIF-1α, and its downstream VEGF-A in an Akt dependent manner. In depleting ASK1 upon hypoxia, TLX decreased and the apoptosis ratio of NB cells was enhanced, while low-ASK1-expressing NB cell lines were refractory in TUNEL assay by using flow cytometry. Interestingly, primary NB spheres cell lines express only high levels of active pASK1Thr-838 but the established cell lines expressed inhibitory pASK1Ser-966, and both could be targeted by ASK1 depletion. We report a novel pro-survival role of ASK1 in the tumorigenic NB cell populations, which may be applied as a therapeutic target, inducing apoptosis specifically in cancer stem cells.
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE 405 30 Gothenburg, Sweden. Electronic address: kspraveen01@gmail.com.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Sobhan
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE 405 30 Gothenburg, Sweden. Electronic address: qiwei.zhai@gu.se.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Zhai
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE 405 30 Gothenburg, Sweden. Electronic address: lydia.green@gu.se.
authors.forename: Lydia C
authors.initials: LC
authors.lastname: Green
authors.affiliation: Program in Neurosciences and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada. Electronic address: loen.hansford@gmail.com.
authors.forename: Loen M
authors.initials: LM
authors.lastname: Hansford
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE 405 30 Gothenburg, Sweden; Oncology Laboratory, Department of Pathology, Sahlgrenska University Hospital, SE 413 45 Gothenburg, Sweden. Electronic address: keiko.funa@gu.se.
authors.forename: Keiko
authors.initials: K
authors.lastname: Funa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000737:chemistry / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016513:Mice, SCID; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001562:Benzimidazoles; D002232:Carbocyanines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D048848:MAP Kinase Kinase Kinase 5; D057093:Orphan Nuclear Receptors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear; D000099162:Endothelial PAS Domain-Containing Protein 1; C088601:NR2E1 protein, human; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; C482858:MAP3K5 protein, human
keywords: ASK1; Apoptosis; HIF-1α; Neuroblastoma; TLX