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.

Targeting GLI factors to inhibit the Hedgehog pathway

“…These characteristics strongly encourage the synergic therapy with itraconazole and ATO for the treatment of de novo Hh-dependent tumors or those with acquired resistance to cyclopamine [94]. Following these studies, the efficacy of ATO in targeting GLI transcription factors has been investigated in MB [93][94][95], pleural mesothelioma [96], malignant rhabdoid tumors [97], osteosarcoma [98], and many others cancer types. Furthermore, growing evidence points to a role for ATO as a modulator of the proliferation and differentiation of cancer cells progenitors by impacting on Hh or Notch signaling [99].…”

Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation

“…These evidence characterized that Shh overexpression was a critical event in breast carcinogenesis [8,9]. In addition, Shh activation induced transcription of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2) and caused a robust increase of glycolytic metabolism in medulloblastoma [10]. The process is mediated by the canonical activation of the Gli transcription factors [10].…”

“…In addition, Shh activation induced transcription of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2) and caused a robust increase of glycolytic metabolism in medulloblastoma [10]. The process is mediated by the canonical activation of the Gli transcription factors [10]. Nevertheless, the exact role of Shh signaling in breast cancer remains unclear.…”

Digging a hole under Hedgehog: downstream inhibition as an emerging anticancer strategy

“…Hh-dependent tumorigenesis and whether metabolic drugs may limit 586 Medulloblastoma growth wasn't addressed in that work. 587 We recently demonstrated that Medulloblastoma cells reprogram 588 glucose metabolism toward aerobic glycolysis mostly via the canonical 589 Gli-dependent pathway [131]. Furthermore, since aerobic glycolysis 590 can be targeted at multiple levels with specific drugs, we attempted to 591 understand if compounds that revert the glucose phenotype are also po-592 tential weapons against MB growth.…”

“…Many of DCA ef-613 fects are linked to the inhibition of HIF1α transcription factor [137]. 614 Since DCA was used in patients with lactic acidosis and in clinical trials 615 of Glioblastoma, we tested its ability to counteract Hedgehog dependent 616 cell proliferation in preclinical models of Shh Medulloblastoma [131]. …”