Licochalcone A is a potent inhibitor of TEL-Jak2-mediated transformation through the specific inhibition of Stat3 activation.
Aberrant activation of Jak/Stat signaling causes a number of hematopoietic disorders and oncogenesis, and therefore the effective inhibitors of the Jak/Stat signaling pathway may be therapeutically useful. TEL-Jak2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. Expression of TEL-Jak2 protects Ba/F3 cells from IL-3 withdrawal-induced apoptotic cell death and leads to IL-3-independent growth. However, its mechanisms remain to be only partially understood. Here, we first found that Licochalcone A, one of the flavonoids isolated from the root of Glycyrrhiza inflate, inhibited TEL-Jak2-mediated cell proliferation and survival in the absence of IL-3. Licochalcone A failed to inhibit the activity of TEL-Jak2, however, this induced apoptosis of TEL-Jak2-transformed cells with a much lower concentration in the absence of IL-3 than in the presence of IL-3. Interestingly, Licochalcone A significantly inhibited the phosphorylation and nuclear localization of Stat3, which is essential for TEL-Jak2-induced cell transformation. These data suggest that Licochalcone A is a specific inhibitor for Stat3 and would be employed for the treatment of various diseases caused by disorders of the Jak/Stat pathway.
Department of Biochemistry, Faculty of Pharmacology, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Megumi
M
Funakoshi-Tago
Kenji
K
Tago
Chiho
C
Nishizawa
Kyoko
K
Takahashi
Tadahiko
T
Mashino
Susumu
S
Iwata
Hideo
H
Inoue
Yoshiko
Y
Sonoda
Tadashi
T
Kasahara
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D047188:Chalcones / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D007938:Leukemia / Q000517:prevention & control; D051379:Mice; D015514:Oncogene Proteins, Fusion; D010936:Plant Extracts; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
D047188:Chalcones; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D010936:Plant Extracts; D050796:STAT3 Transcription Factor; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein; C070840:licochalcone A