Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth.
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.
Baryawno
Ninib
N
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. ninib.baryawno@ki.se
Sveinbjörnsson
Baldur
B
Eksborg
Staffan
S
Chen
Ching-Shih
CS
Kogner
Per
P
Johnsen
John Inge
JI
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008527:Medulloblastoma / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D051153:Wnt Proteins / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism*
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; C401859:temsirolimus; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus