Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis

Daniela Annibali; Jonathan R Whitfield; Emilia Favuzzi; Toni Jauset; Erika Serrano; Isabel Cuartas; Sara Redondo-Campos; Gerard Folch; Alba Gonzàlez-Juncà; Nicole M Sodir; Daniel Massó-Vallés; Marie-Eve Beaulieu; Lamorna B Swigart; Margaret M Mc Gee; Maria Patrizia Somma; Sergio Nasi; Joan Seoane; Gerard I Evan; Laura Soucek

doi:10.1038/ncomms5632

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis

Nat Commun. 2014 Aug 18:5:4632. doi: 10.1038/ncomms5632.

Authors

Daniela Annibali¹, Jonathan R Whitfield², Emilia Favuzzi³, Toni Jauset⁴, Erika Serrano⁴, Isabel Cuartas⁴, Sara Redondo-Campos⁴, Gerard Folch⁴, Alba Gonzàlez-Juncà⁴, Nicole M Sodir⁵, Daniel Massó-Vallés⁴, Marie-Eve Beaulieu⁴, Lamorna B Swigart⁶, Margaret M Mc Gee⁷, Maria Patrizia Somma³, Sergio Nasi³, Joan Seoane⁸, Gerard I Evan⁹, Laura Soucek⁴

Affiliations

¹ 1] Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA [2] Istituto di Biologia, Medicina Molecolare e NanoBiotecnologie, C.N.R., Dipartimento di Biologia e Biotecnologie, Università La Sapienza, 00185 Rome, Italy [3].
² 1] Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, 08035 Barcelona, Spain [2] Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), 08193 Barcelona, Spain [3].
³ Istituto di Biologia, Medicina Molecolare e NanoBiotecnologie, C.N.R., Dipartimento di Biologia e Biotecnologie, Università La Sapienza, 00185 Rome, Italy.
⁴ 1] Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, 08035 Barcelona, Spain [2] Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), 08193 Barcelona, Spain.
⁵ 1] Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA [2] Department of Biochemistry, Sanger Building, University of Cambridge, Cambridge CB2 1QW, UK.
⁶ Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA.
⁷ UCD School of Biomolecular &Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
⁸ 1] Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, 08035 Barcelona, Spain [2] Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), 08193 Barcelona, Spain [3] Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
⁹ Department of Biochemistry, Sanger Building, University of Cambridge, Cambridge CB2 1QW, UK.

Abstract

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells.

Publication types

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

MeSH terms

Animals
Apoptosis / physiology
Astrocytoma / pathology*
Astrocytoma / physiopathology
Astrocytoma / therapy
Brain Neoplasms / pathology*
Brain Neoplasms / physiopathology
Brain Neoplasms / therapy
Cell Line, Tumor
Cell Proliferation / physiology
Disease Models, Animal
Glioblastoma / pathology*
Glioblastoma / physiopathology
Glioblastoma / therapy
Glioma / pathology*
Glioma / physiopathology
Glioma / therapy
Heterografts
Humans
Mice
Mice, Transgenic
Mitosis / physiology*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / physiology
Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
Proto-Oncogene Proteins c-myc / physiology
Ubiquitin-Activating Enzymes / physiology

Substances

MYC protein, human
Myc protein, mouse
Proto-Oncogene Proteins c-myc
SAE1 protein, mouse
PTPN1 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Ptpn1 protein, mouse
SAE1 protein, human
Ubiquitin-Activating Enzymes

Abstract

Publication types

MeSH terms

Substances

Grants and funding