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Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

  1. Paolo Salomonia,2

Author Affiliations

  1. aSamantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, United Kingdom;
  2. bDepartment of Experimental and Clinical Sciences, Aging Research Center (Centro Scienze dell'Invecchiamento), University G. d’Annunzio, 66013 Chieti-Pescara, Italy;
  3. cInstitute of Neurology, University College London, London WC1N 3BG, United Kingdom;
  4. dKarolinska Institute, SE-171 77 Stockholm, Sweden;
  5. eMedical Research Council Toxicology Unit, Leicester LE1 7HB, United Kingdom;
  6. fBarts Cancer Institute, Queen Mary University, London E1 2AD, United Kingdom; and
  7. gDeutsches Zentrum für Neurodegenerative Erkrankungen, 53175 Bonn, Germany

  1. Edited by Douglas R. Green, St. Jude Children's Research Hospital, Memphis, TN, and accepted by the Editorial Board December 10, 2014 (received for review July 11, 2014)

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    Significance

    Brain cancer is one of the deadliest human tumors and is characterized by several genetic changes leading to impairment of tumor suppressive pathways and oncogene activation. These genetic alterations promote subsequent molecular changes, including modifications of cellular metabolism, which are believed to contribute to cancer pathogenesis. Conversely, the role of metabolic changes in regulation of genomic stability in brain cancer has not been investigated. Our work shows that alterations of mitochondrial metabolism promote genetic loss of the p53 tumor suppressor and transformation via a mechanism involving reactive oxygen species. Overall, our findings suggest a causative link between metabolic alterations and loss of tumor suppressive control in the central nervous system, with implications for our understanding of brain cancer pathogenesis.

    Abstract

    Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.

    Footnotes

    • ↵1V.G., S.G., and N.V.H. contributed equally to this work.

    • ↵2To whom correspondence should be addressed. Email: p.salomoni@ucl.ac.uk.

    • Author contributions: S. Brandner, V.D.L., and P.S. designed research; S. Bartesaghi, V.G., S.G., N.V.H., J.B., J.S., D.A., M.C., and S. Brandner performed research; A.K., L.M.M., P.N., and V.D.L. contributed new reagents/analytic tools; S. Bartesaghi, V.G., S.G., N.V.H., J.B., J.S., D.A., M.C., S. Brandner, V.D.L., and P.S. analyzed data; and S. Bartesaghi, V.G., S. Brandner, V.D.L., and P.S. wrote the paper.

    • The authors declare no conflict of interest.

    • This article is a PNAS Direct Submission. D.R.G. is a guest editor invited by the Editorial Board.

    • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1413165112/-/DCSupplemental.