title: The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors.
abstract: Persistent activation of Stat3 is oncogenic and is prevalent in a wide variety of human cancers. Chronic cytokine stimulation is associated with Stat3 activation in some tumors, implicating cytokine receptor-associated Jak family kinases. Using Jak2 inhibitors, we demonstrate a central role of Jaks in modulating basal and cytokine-induced Stat3 activation in human solid tumor cell lines. Inhibition of Jak2 activity is associated with abrogation of Stat3 nuclear translocation and tumorigenesis. The Jak2 inhibitor AZD1480 suppresses the growth of human solid tumor xenografts harboring persistent Stat3 activity. We demonstrate the essential role of Stat3 downstream of Jaks by inhibition of tumor growth using short hairpin RNA targeting Stat3. Our data support a key role of Jak kinase activity in Stat3-dependent tumorigenesis.
authors: Molecular Medicine, Beckman Research Institute, Irell & Manella Graduate School of Biological Sciences, City of Hope Cancer Center, Duarte, CA 91010, USA.
authors: Michael
authors: M
authors: Hedvat
authors: Dennis
authors: D
authors: Huszar
authors: Andreas
authors: A
authors: Herrmann
authors: Joseph M
authors: JM
authors: Gozgit
authors: Anne
authors: A
authors: Schroeder
authors: Adam
authors: A
authors: Sheehy
authors: Ralf
authors: R
authors: Buettner
authors: David
authors: D
authors: Proia
authors: Claudia M
authors: CM
authors: Kowolik
authors: Hong
authors: H
authors: Xin
authors: Brian
authors: B
authors: Armstrong
authors: Geraldine
authors: G
authors: Bebernitz
authors: Shaobu
authors: S
authors: Weng
authors: Lin
authors: L
authors: Wang
authors: Minwei
authors: M
authors: Ye
authors: Kristen
authors: K
authors: McEachern
authors: Huawei
authors: H
authors: Chen
authors: Deborah
authors: D
authors: Morosini
authors: Kirsten
authors: K
authors: Bell
authors: Marat
authors: M
authors: Alimzhanov
authors: Stephanos
authors: S
authors: Ioannidis
authors: Patricia
authors: P
authors: McCoon
authors: Zhu A
authors: ZA
authors: Cao
authors: Hua
authors: H
authors: Yu
authors: Richard
authors: R
authors: Jove
authors: Michael
authors: M
authors: Zinda
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C545606:AZD 1480; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2