Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways

摘要

Medulloblastomas are the most frequent malignant brain tumors in children. Sunitinib is an oral multitargeted tyrosine kinase inhibitor used in clinical trials as an antiangiogenic agent for cancer therapy. In this report, we demonstrate that sunitinib induced apoptosis and inhibited cell proliferation of both a short-term primary culture (VC312) and an established cell line (Daoy) of human medulloblastomas. Sunitinib treatment resulted in the activation of caspase-3 and cleavage of PARP, and upregulation of pro-apoptotic genes, Bak and Bim, as well as inhibiting expression of survivin, an anti-apoptotic protein. Sunitinib treatment also down-regulated cyclin E, D2 and D3, and up-regulated p21Cip1, all of which are involved in regulating cell cycle. In addition, it inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) and AKT (protein kinase B) in the tumor cells. De-phosphorylation of STAT3 (Tyr705) induced by sunitinib was contributed by a reduction in activities of JAK2 and Src. Additionally, sodium vanadate, an inhibitor of protein tyrosine phosphatases, partially blocked the inhibition of phosphorylated STAT3 by sunitinib. Loss of phosphorylated AKT after sunitinib treatment was accompanied by decreased phosphorylation of downstream proteins, GSK-3β and mTOR. Expression of a constitutively activated STAT3 mutant or myristoylated AKT partially blocked the effects of sunitinib in these tumor cells. Sunitinib also inhibited the migration of medulloblastoma tumor cells in vitro. These findings suggest that potential use of sunitinib for treatment of pediatric medulloblastomas.