Small-Molecule Inhibitors of Phosphatidylinositol 3-Kinase/Akt Signaling Inhibit Wnt/β-Catenin Pathway Cross-Talk and Suppress Medulloblastoma Growth

Abstract

Activation of the β-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 β-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 glycogen synthase kinase 3β (GSK-3β) was detected by immunohistochemistry in all primary medulloblastomas examined (n = 41). Small-molecule inhibitors targeting the PI3K/Akt signaling pathway affected β-catenin signaling by inhibition of GSK-3β activity, resulting in cytoplasmic retention of β-catenin and reduced expression of its target genes cyclin D1 and c-Myc. The PDK1 inhibitor OSU03012 induced mitochondrialdependent 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 β-catenin pathways in medulloblastoma and rationalize the PI3K/Akt signaling pathway as a therapeutic target in treatment of this disease. Cancer Res; 70(1); 266-76. ©2010 AACR.

Lgr4 Promotes Glioma Cell Proliferation through Activation of Wnt Signaling

“…Besides, activating mutations in the β-catenin gene have identified and was shown to be involved in the development of a subset of medulloblastomas (Zurawel et al, 1998). In addition, several extracellular signals were exhibited to promote or repress glioma cell proliferation through regulation of Wnt/β-catenin (Xie et al, 2004;Baryawno et al, 2010). Therefore, these findings demonstrate the importance of Wnt signaling pathway as a therapeutic target in treatment of glioma.…”

“…For instance, in human breast cancer, cytoplasmic and nuclear localization of β-catenin were shown to predict a poor outcome (Deng et al, 2002). In human gliomas, nuclear immunoreactivity of β-catenin is established as a favorable-risk indicator in a subgroup of medulloblastomas (Baryawno et al, 2010). Besides, activating mutations in the β-catenin gene have identified and was shown to be involved in the development of a subset of medulloblastomas (Zurawel et al, 1998).…”

GPR48 Promotes Multiple Cancer Cell Proliferation via Activation of Wnt Signaling

“…For instance, in human breast cancer, cytoplasmic and nuclear localization of b-catenin were shown to predict a poor outcome (Deng et al, 2002). In human medulloblastomas, nuclear immunoreactivity of b-catenin is established as a favorable-risk indicator (Baryawno et al, 2010). Therefore, Wnt signaling pathway has become a therapeutic target for the control of tumor progression (Niehrs et al, 2012).…”

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

“…Thus, targeting PI3K signalling may represent an attractive novel approach to develop novel therapies for medulloblastoma. Indeed, there now exist different pharmacological inhibitors of PI3K, which have entered clinical trials for adult cancer and could, in the future, be also considered for medulloblastoma (12,(45)(46)(47).…”

“…Receptor tyrosine kinases (RTKs) such as ErbB-2, ErbB-4, insulin-like growth factor-I receptor (IGF-IR), and platelet-derived growth factor receptor (PDGFR) have been shown to be expressed and to control cell proliferation, survival, and the development of metastasis in human medulloblastoma cells (1,5). New therapies for medulloblastoma are emerging, which are based on blocking signalling by these RTKs to some of their downstream signalling targets such as phosphoinositide 3-kinase (PI3K), protein kinase B (PKB)/Akt, the mammalian target of rapamycin (mTOR), and mitogen-activated extracellular signal-regulated kinase activating kinase (MEK) (6)(7)(8)(9)(10)(11)(12).…”