Bortezomib reverses a post-translational mechanism of tumorigenesis for Patched1 haploinsufficiency in medulloblastoma

Eri Taniguchi, Jung Cho Min, Benjamin R. Arenkiel, Mark S. Hansen, Omar J. Rivera, Amanda T. McCleish, Stephen J. Qualman, Denis C. Guttridge, Matthew P. Scott, Mario R. Capecchi, Charles Keller

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background. Tumor initiation has been attributed to haploinsuf-ficiency 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.

Original languageEnglish (US)
Pages (from-to)136-144
Number of pages9
JournalPediatric Blood and Cancer
Volume53
Issue number2
DOIs
StatePublished - Aug 2009
Externally publishedYes

Fingerprint

Haploinsufficiency
Medulloblastoma
Carcinogenesis
Neoplasms
Hedgehog Proteins
Cerebellar Neoplasms
Proteasome Inhibitors
Rhabdomyosarcoma
Proteasome Endopeptidase Complex
Cerebellum
Proteins
Down-Regulation
Bortezomib
Therapeutics
Growth

Keywords

  • Bortezomib
  • Haploinsufficiency
  • Hedgehog
  • Medulloblastoma
  • Patched1
  • Proteasome

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Taniguchi, E., Min, J. C., Arenkiel, B. R., Hansen, M. S., Rivera, O. J., McCleish, A. T., ... Keller, C. (2009). Bortezomib reverses a post-translational mechanism of tumorigenesis for Patched1 haploinsufficiency in medulloblastoma. Pediatric Blood and Cancer, 53(2), 136-144. https://doi.org/10.1002/pbc.21968

Bortezomib reverses a post-translational mechanism of tumorigenesis for Patched1 haploinsufficiency in medulloblastoma. / Taniguchi, Eri; Min, Jung Cho; 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.

In: Pediatric Blood and Cancer, Vol. 53, No. 2, 08.2009, p. 136-144.

Research output: Contribution to journalArticle

Taniguchi, E, Min, JC, Arenkiel, BR, Hansen, MS, Rivera, OJ, McCleish, AT, Qualman, SJ, Guttridge, DC, Scott, MP, Capecchi, MR & Keller, C 2009, 'Bortezomib reverses a post-translational mechanism of tumorigenesis for Patched1 haploinsufficiency in medulloblastoma', Pediatric Blood and Cancer, vol. 53, no. 2, pp. 136-144. https://doi.org/10.1002/pbc.21968
Taniguchi, Eri ; Min, Jung Cho ; 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. / Bortezomib reverses a post-translational mechanism of tumorigenesis for Patched1 haploinsufficiency in medulloblastoma. In: Pediatric Blood and Cancer. 2009 ; Vol. 53, No. 2. pp. 136-144.
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