Premium
Bortezomib reverses a post‐translational mechanism of tumorigenesis for patched1 haploinsufficiency in medulloblastoma
Author(s) -
Taniguchi Eri,
Cho Min Jung,
Arenkiel Benjamin R.,
Hansen Mark S.,
Rivera Omar J.,
McCleish Amanda T.,
Qualman Stephen J.,
Guttridge Denis C.,
Scott Matthew P.,
Capecchi Mario R.,
Keller Charles
Publication year - 2009
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.21968
Subject(s) - haploinsufficiency , medulloblastoma , cancer research , vismodegib , medicine , carcinogenesis , rhabdomyosarcoma , biology , hedgehog signaling pathway , cancer , microbiology and biotechnology , signal transduction , pathology , genetics , sarcoma , phenotype , gene
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. Pediatr Blood Cancer 2009;53:136–144. © 2009 Wiley‐Liss, Inc.