title: Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas.
abstract: Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr(705)) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Van Meter
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Kowolik
authors.forename: Nilesh
authors.initials: N
authors.lastname: Mepani
authors.forename: Janni
authors.initials: J
authors.lastname: Mirosevich
authors.forename: Sangkil
authors.initials: S
authors.lastname: Nam
authors.forename: Mike Y
authors.initials: MY
authors.lastname: Chen
authors.forename: Gary
authors.initials: G
authors.lastname: Tye
authors.forename: Mark
authors.initials: M
authors.lastname: Kirschbaum
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001557:Benzenesulfonates / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D056741:Cyclin D; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D056741:Cyclin D; D016213:Cyclins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D050796:STAT3 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib