The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors.
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.
Hedvat
Michael
M
Molecular Medicine, Beckman Research Institute, Irell & Manella Graduate School of Biological Sciences, City of Hope Cancer Center, Duarte, CA 91010, USA.
Huszar
Dennis
D
Herrmann
Andreas
A
Gozgit
Joseph M
JM
Schroeder
Anne
A
Sheehy
Adam
A
Buettner
Ralf
R
Proia
David
D
Kowolik
Claudia M
CM
Xin
Hong
H
Armstrong
Brian
B
Bebernitz
Geraldine
G
Weng
Shaobu
S
Wang
Lin
L
Ye
Minwei
M
McEachern
Kristen
K
Chen
Huawei
H
Morosini
Deborah
D
Bell
Kirsten
K
Alimzhanov
Marat
M
Ioannidis
Stephanos
S
McCoon
Patricia
P
Cao
Zhu A
ZA
Yu
Hua
H
Jove
Richard
R
Zinda
Michael
M
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*
C545606:AZD 1480; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2