Bortezomib reverses a post-translational mechanism of tumorigenesis for patched1 haploinsufficiency in medulloblastoma

Pediatr Blood Cancer. 2009 Aug;53(2):136-44. doi: 10.1002/pbc.21968.


Background: Tumor initiation has been attributed to haploinsufficiency at a single locus for a large number of cancers. Patched1 (Ptc1) was one of the first such loci, and Ptc1 haploinsufficiency has been asserted to lead to medulloblastoma and rhabdomyosarcoma in mice.

Procedure: To study the role of Ptc1 in cerebellar tumor development and to create a preclinical therapeutic platform, we have generated a conditional Ptc1 haploinsufficiency model of medulloblastoma by inactivating Ptc1 in Pax7-expressing cells of the cerebellum.

Results: These mice developed exclusively medulloblastoma. We show that despite the presence of transcription of Ptc1, Ptc1 protein is nearly undetectable or absent in tumors. Our results suggest that Ptc1 loss of function is complete, but achieved at the protein level rather than by the classic genetic two-hit mechanism or a strict half-dosage genetic haploinsufficiency mechanism. Furthermore, we found that bortezomib, a 26S proteasome inhibitor, had a significant anti-tumor activity in vitro and in vivo, which was accompanied by restoration of Ptc1 protein and downregulation of the hedgehog signaling pathway. The same effect was seen for both human and mouse medulloblastoma tumor cell growth.

Conclusions: These results suggest that proteasome inhibition is a potential new therapeutic approach in medulloblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cerebellar Neoplasms / genetics*
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • Hedgehog Proteins / drug effects
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Loss of Heterozygosity / drug effects
  • Loss of Heterozygosity / genetics
  • Medulloblastoma / genetics*
  • Mice
  • Mice, Knockout
  • PAX7 Transcription Factor
  • Patched Receptors
  • Patched-1 Receptor
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Isoforms
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / physiology*
  • Pyrazines / pharmacology*
  • Receptors, Cell Surface / drug effects*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism


  • Antineoplastic Agents
  • Boronic Acids
  • Hedgehog Proteins
  • PAX7 Transcription Factor
  • PTCH1 protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Pax7 protein, mouse
  • Protein Isoforms
  • Ptch1 protein, mouse
  • Pyrazines
  • Receptors, Cell Surface
  • Bortezomib
  • Proteasome Endopeptidase Complex