title: Inhibition of PI3K Signalling Selectively Affects Medulloblastoma Cancer Stem Cells.
abstract: Medulloblastoma is the most common malignant brain tumor of childhood. Although survival has slowly increased in the past years, the prognosis of these patients remains unfavourable. In this context, it has been recently shown that the intracellular signaling pathways activated during embryonic cerebellar development are deregulated in MDB. One of the most important is PI3K/AKT/mTOR, implicated in cell proliferation, survival, growth, and protein synthesis. Moreover, a fraction of MDB cells has been shown to posses stemlike features, to express typical neuronal precursor markers (Nestin and CD133), and to be maintained by the hypoxic cerebellar microenvironment. This subpopulation of MDB cells is considered to be responsible for treatment resistance and recurrence. In this study, we evaluated the effects of PI3K/AKT pathway inhibition on primary cultures of MDB and particularly on the cancer stem cell (CSC) population (CD133(+)). PI3K inhibition was able to counteract MDB cell growth and to promote differentiation of stemlike MDB cells. Moreover, PI3K/AKT pathway suppression induced dramatic cell death through activation of the mitochondrial proapoptotic cascade. Finally, analysis on the stem cells fraction revealed that the MDB CSC population is more sensitive to PI3K targeting compared to the whole cancerous population and its nonstem cell counterpart.
authors.affiliation: Istituto di Ricerca Pediatrica Città della Speranza (IRP), Corso Stati Uniti 4, 35127 Padova, Italy ; Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Frasson
authors.affiliation: Istituto di Ricerca Pediatrica Città della Speranza (IRP), Corso Stati Uniti 4, 35127 Padova, Italy ; Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Rampazzo
authors.affiliation: Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Accordi
authors.affiliation: Department of Neuroscience, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Beggio
authors.affiliation: Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pistollato
authors.affiliation: Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Istituto di Ricerca Pediatrica Città della Speranza (IRP), Corso Stati Uniti 4, 35127 Padova, Italy ; Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Persano
mesh_terms: D017209:Apoptosis; D001921:Brain / Q000166:cytology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism*; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one