Research Article

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

  1. Eri Taniguchi PhD1,
  2. Min Jung Cho MD1,
  3. Benjamin R. Arenkiel PhD2,
  4. Mark S. Hansen2,
  5. Omar J. Rivera PhD1,
  6. Amanda T. McCleish1,
  7. Stephen J. Qualman MD3,
  8. Denis C. Guttridge PhD4,
  9. Matthew P. Scott PhD5,
  10. Mario R. Capecchi PhD2,
  11. Charles Keller MD1,*

Article first published online: 11 FEB 2009

DOI: 10.1002/pbc.21968

Issue

Pediatric Blood & Cancer

Pediatric Blood & Cancer

Volume 53, Issue 2, pages 136–144, August 2009

Additional Information

How to Cite

Taniguchi, E., Cho, M. J., Arenkiel, B. R., Hansen, M. S., Rivera, O. J., McCleish, A. T., Qualman, S. J., Guttridge, D. C., Scott, M. P., Capecchi, M. R. and Keller, C. (2009), Bortezomib reverses a post-translational mechanism of tumorigenesis for patched1 haploinsufficiency in medulloblastoma. Pediatr. Blood Cancer, 53: 136–144. doi: 10.1002/pbc.21968

Author Information

  1. 1

    Departments of Cellular & Structural Biology and Pediatrics, Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas

  2. 2

    Howard Hughes Medical Institute and Department of Human Genetics, University of Utah, Salt Lake City, Utah

  3. 3

    Department of Laboratory Medicine, Columbus Children's Hospital, Children's Research Institute, Columbus, Ohio

  4. 4

    Human Cancer Genetics Program, The Ohio State University College of Medicine, Columbus, Ohio

  5. 5

    Howard Hughes Medical Institute and Departments of Developmental Biology, Genetics, and Bioengineering, Stanford University School of Medicine, Stanford, California

*Greehey Children's Cancer Research Institute, University of Texas Health Science Center, 8403 Floyd Curl Drive, MC-7784, San Antonio, TX 78229-3900.

  1. †

    The authors declare no conflicts of interest.

Publication History

  1. Issue published online: 9 JUN 2009
  2. Article first published online: 11 FEB 2009
  3. Manuscript Accepted: 13 JAN 2009
  4. Manuscript Received: 24 DEC 2008

Funded by

  • Pediatric Brain Tumor Foundation of the United States
  • St. Baldrick's Foundation
  • National Brain Tumor Society
  • Cancer Therapy and Research Center. Grant Number: P30CA54174
  • Huntsman Cancer Institute's Center for Children

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Keywords:

  • bortezomib;
  • haploinsufficiency;
  • hedgehog;
  • medulloblastoma;
  • patched1;
  • proteasome

Abstract

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.

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