Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth

Cancer Res. 2010 Jan 1;70(1):266-76. doi: 10.1158/0008-5472.CAN-09-0578. Epub 2009 Dec 22.


Activation of the beta-catenin and receptor kinase pathways occurs often in medulloblastoma, the most common pediatric malignant brain tumor. In this study, we show that molecular cross-talk between the beta-catenin and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways is crucial to sustain medulloblastoma pathophysiology. Constitutive activation of phosphoinositide-dependent protein kinase 1 (PDK1), Akt, and phosphorylation of [corrected] glycogen synthase kinase 3beta (GSK-3beta) was detected by immunohistochemistry in all primary medulloblastomas examined (n = 41). Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected beta-catenin signaling by activation [corrected] of GSK-3beta, [corrected] resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc. The PDK1 inhibitor OSU03012 induced mitochondrial-dependent apoptosis of medulloblastoma cells and enhanced the cytotoxic effects of chemotherapeutic drugs in a synergistic or additive manner. In vivo, OSU03012 inhibited the growth of established medulloblastoma xenograft tumors in a dose-dependent manner and augmented the antitumor effects of mammalian target of rapamycin inhibitor CCI-779. These findings demonstrate the importance of cross-talk between the PI3K/Akt and beta-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cerebellar Neoplasms / metabolism
  • Cerebellar Neoplasms / physiopathology*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunohistochemistry
  • Medulloblastoma / metabolism
  • Medulloblastoma / physiopathology*
  • Mice
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Small Interfering
  • Receptor Cross-Talk / drug effects
  • Receptor Cross-Talk / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • Transfection
  • Wnt Proteins / drug effects
  • Wnt Proteins / metabolism*
  • Xenograft Model Antitumor Assays
  • beta Catenin / drug effects
  • beta Catenin / metabolism*


  • Antineoplastic Agents
  • RNA, Small Interfering
  • Wnt Proteins
  • beta Catenin
  • temsirolimus
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Sirolimus