title: Druggable glycolytic requirement for Hedgehog-dependent neuronal and medulloblastoma growth.
abstract: Aberrant activation of SHH pathway is a major cause of medulloblastoma (MB), the most frequent brain malignancy of the childhood. A few Hedgehog inhibitors, all antagonizing the membrane transducer Smo, have been approved or are under clinical trials for the treatment of human MB. However, the efficacy of these drugs is limited by the occurrence of novel mutations or by activation of downstream or non-canonical Hedgehog components. Thus, the identification of novel druggable downstream pathways represents a critical step to overcome this problem. In the present work we demonstrate that aerobic glycolysis is a valuable HH-dependent downstream target, since its inhibition significantly counteracts the HH-mediated growth of normal and tumor cells. Hedgehog activation induces transcription of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), two key gatekeepers of glycolysis. The process is mediated by the canonical activation of the Gli transcription factors and causes a robust increase of extracellular lactate concentration. We show that inhibition of glycolysis at different levels blocks the Hedgehog-induced proliferation of granule cell progenitors (GCPs), the cells from which medulloblastoma arises. Remarkably, we demonstrate that this glycolytic transcriptional program is also upregulated in SHH-dependent tumors and that pharmacological targeting with the pyruvate kinase inhibitor dichloroacetate (DCA) efficiently represses MB growth in vitro and in vivo. Together, these data illustrate a previously uncharacterized pharmacological strategy to target Hedgehog dependent growth, which can be exploited for the treatment of medulloblastoma patients.
authors.affiliation: a Department of Molecular Medicine ; Sapienza University of Rome.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Magno
authors.forename: Daniela
authors.initials: D
authors.lastname: Manzi
authors.forename: Davide
authors.initials: D
authors.lastname: D'Amico
authors.forename: Sonia
authors.initials: S
authors.lastname: Coni
authors.forename: Alberto
authors.initials: A
authors.lastname: Macone
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Enzo
authors.initials: E
authors.lastname: Agostinelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003999:Dichloroacetic Acid / Q000494:pharmacology / Q000627:therapeutic use; D006019:Glycolysis / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014184:Transplantation, Homologous; D000071676:Zinc Finger Protein GLI1
chemical_list: D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D006593:Hexokinase; D011770:Pyruvate Kinase
keywords: 2DG, 2-deoxy-D-glucose; 3-BrPA, 3-Bromopyruvate; ACC, Acetyl-CoA carboxylase; ATO, arsenic trioxide; DCA; DCA, dichloroacetate; EGL, external granular layer; GCPs, granule cells progenitors; HH, Hedgehog; HK2, Hexokinase 2; Hedgehog; IGL, internal granular layer; MB, Medulloblastoma; PARP, poly( ADP-ribose) polymerase; PKM2, Pyruvate Kinase M2; Ptch1, Patched1; ROS, reactive oxygen species; SHH, Sonic Hedgehog; Smo, Smoothened; Sufu, suppressor of fused; cerebellum; glycolysis; medulloblastoma; metabolism