TY - JOUR
T1 - Licochalcone A is a potent inhibitor of TEL-Jak2-mediated transformation through the specific inhibition of Stat3 activation
AU - Funakoshi-Tago, Megumi
AU - Tago, Kenji
AU - Nishizawa, Chiho
AU - Takahashi, Kyoko
AU - Mashino, Tadahiko
AU - Iwata, Susumu
AU - Inoue, Hideo
AU - Sonoda, Yoshiko
AU - Kasahara, Tadashi
N1 - Funding Information:
We thank Mr. T. Tokumasu and Ms. I. Michikawa for their technical assistance. We also thank Ms. Kayoko Tani and Mr. Yusuke Sumiyoshi for providing us Licochalcone A and its derivatives. This work was supported in part by grants (16390024, 9590075, 19790071) from MEXT and the Hi-Tech Research Center Project for Private Universities in Japan.
PY - 2008/12/15
Y1 - 2008/12/15
N2 - 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.
AB - 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.
KW - Glycyrrhiza inflate
KW - Licochalcone
KW - Stat3
KW - TEL-Jak2
UR - http://www.scopus.com/inward/record.url?scp=56549085955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=56549085955&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2008.09.012
DO - 10.1016/j.bcp.2008.09.012
M3 - Article
C2 - 18848530
AN - SCOPUS:56549085955
SN - 0006-2952
VL - 76
SP - 1681
EP - 1693
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 12
ER -
