Proteasome inhibition—a new target for brain tumours

Abstract

The Ubiquitin Proteasome Pathway (UPP) is responsible for intracellular protein degradation in all eukaryotic cells 1 . A main function of the proteasome is to remove damaged and short-lived regulatory proteins from the cell that would otherwise accumulate and induce cell death or impair cellular function 2 . The UPP is also required to control the half-lives of regulatory ‘house-keeping’ proteins that are necessary in different concentrations depending on the cell state 2 . This highly controlled system is essential for the maintenance of protein homeostasis. As such, deregulation of the UPP has been implicated in many disease processes. Upregulation of the UPP has been linked to cancer while downregulation of the UPP has been implicated in neurodegenerative diseases such as Alzheimer’s disease 3 , 4 . In the context of malignancy, proteins involved in cellular differentiation, DNA damage repair, cell cycle regulation and apoptosis are targets of the UPP 5 . Many products of tumour suppressor genes and oncogenes are also subject to regulation by this pathway, and dysregulation of the UPP has been implicated in renal carcinoma, colorectal cancer, cervical cancer and glioma 4 , 6 . The UPP has also been shown to contribute to the neurogenesis of cerebellar progenitor cells due to its role in regulating the degradation of transcription factors involved in neuronal cell differentiation 7 . The focus of our work was to study the activity of the UPP in medulloblastoma tumours (MBs), a cancer that originates from the cerebellum 8 . Evidence from Tsvetkof et al. suggests that malignant cells are addicted to the UPP for survival 9 , and are therefore more sensitive to its inhibition than normal cells. Our recent work confirms this and shows that high proteasome activity in MB cells is associated with poor prognosis 8 . MB is the most common solid primary malignant brain tumour of children 10 . MBs have recently been classified into four molecular subgroups. These are wingless (WNT-best prognosis), sonic hedgehog (SHH-intermediate prognosis), group 3 (G3-worst prognosis) and group 4 (G4-intermediate prognosis). Aggressive medulloblastoma, G3 and G4, occurs in infants and young children and are frequently metastatic. While current treatment (surgical resection followed by chemotherapy and radiotherapy) has increased survival over the last two decades, a third of patients remain incurable and others suffer long term side effects from treatment 11 .