title: Sorafenib inhibits endogenous and IL-6/S1P induced JAK2-STAT3 signaling in human neuroblastoma, associated with growth suppression and apoptosis.
abstract: Neuroblastoma is the most common extracranial solid tumor in the pediatric population. Sorafenib (Nexavar), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in certain types of cancers. Here, we tested antitumor effects of sorafenib (≤ 10 µM) on four human neuroblastoma cell lines, CHLA255, CHLA171, CHLA90 and SK-N-AS. Sorafenib inhibited cell proliferation and induced apoptosis of neuroblastoma tumor cells in a dose-dependent manner. Sorafenib inhibited phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) proteins at Tyr705 in these cells, associated with inhibition of phosphorylated JAK2, an upstream kinase that mediates STAT3 phosphorylation. Expression of a constitutively-activated STAT3 mutant (pSTAT3-C) partially blocked the antitumor effects of sorafenib on neuroblastoma cells. Sorafenib also inhibited the phosphorylation of STAT3 induced by IL-6 and sphingosine-1-phosphate (S1P), a recently identified regulator for STAT3, in these tumor cells. Moreover, sorafenib downregulated phosphorylation of MAPK (p44/42) in neuroblastoma cells, consistent with inhibition of their upstream regulators MEK1/2. Sorafenib inhibited expression of cyclin E, cyclin D1/D2/D3, key regulators for cell cycle, and the antiapoptotic proteins Mcl-1 and survivin. Finally, sorafenib suppressed the growth of human neuroblastoma cells in a mouse xenograft model. Taken together, these findings suggest the potential use of sorafenib for the treatment of pediatric neuroblastomas.
authors.affiliation: Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Veronica
authors.initials: V
authors.lastname: Jove
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Sangkil
authors.initials: S
authors.lastname: Nam
authors.forename: Yibing
authors.initials: Y
authors.lastname: Xu
authors.forename: Tasnim
authors.initials: T
authors.lastname: Ara
authors.forename: Yves A
authors.initials: YA
authors.lastname: DeClerck
authors.forename: Robert
authors.initials: R
authors.lastname: Seeger
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001557:Benzenesulfonates; D015850:Interleukin-6; D008246:Lysophospholipids; D010671:Phenylurea Compounds; D011725:Pyridines; D050796:STAT3 Transcription Factor; D009536:Niacinamide; C060506:sphingosine 1-phosphate; D000077157:Sorafenib; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D013110:Sphingosine