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


METHODS
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.
Taniguchi
Eri
E
Department of Cellular & Structural Biology, Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Cho
Min Jung
MJ
Arenkiel
Benjamin R
BR
Hansen
Mark S
MS
Rivera
Omar J
OJ
McCleish
Amanda T
AT
Qualman
Stephen J
SJ
Guttridge
Denis C
DC
Scott
Matthew P
MP
Capecchi
Mario R
MR
Keller
Charles
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000235:genetics*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D053823:Hedgehog Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D019656:Loss of Heterozygosity / Q000187:drug effects / Q000235:genetics; D008527:Medulloblastoma / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D051763:PAX7 Transcription Factor; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D011719:Pyrazines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D053823:Hedgehog Proteins; D051763:PAX7 Transcription Factor; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C497322:Pax7 protein, mouse; D020033:Protein Isoforms; C000606240:Ptch1 protein, mouse; D011719:Pyrazines; D011956:Receptors, Cell Surface; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex