Druggable glycolytic requirement for Hedgehog-dependent neuronal and medulloblastoma growth

Laura Di Magno, Daniela Manzi, Davide D'Amico, Sonia Coni, Alberto Macone, Paola Infante, Lucia Di Marcotullio, Enrico De Smaele, Elisabetta Ferretti, Isabella Screpanti, Enzo Agostinelli, Alberto Gulino, Gianluca Canettieri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3404-3413
Number of pages10
JournalCell Cycle
Volume13
Issue number21
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • Cerebellum
  • DCA
  • Glycolysis
  • Hedgehog
  • Medulloblastoma
  • Metabolism

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology
  • Medicine(all)

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