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Frequent STAT3 activation is associated with Mcl‐1 expression in nasal NK‐cell lymphoma
Author(s) -
TSUTSUI M.,
YASUDA H.,
SUTO H.,
IMAI H.,
ISOBE Y.,
SASAKI M.,
KOJIMA Y.,
OSHIMI K.,
SUGIMOTO K.
Publication year - 2010
Publication title -
international journal of laboratory hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.705
H-Index - 55
eISSN - 1751-553X
pISSN - 1751-5521
DOI - 10.1111/j.1751-553x.2009.01204.x
Subject(s) - cancer research , lymphoma , stat3 , apoptosis , cell , t cell lymphoma , biology , immunology , biochemistry , genetics
Summary Nasal natural killer (NK)‐cell lymphoma was resistant to various antitumor agents. Although high expression of p‐glycoprotein has been reported, other molecular mechanism of the chemo‐resistance is largely unknown. Activation of STAT3 and expression of major apoptosis‐related proteins Bcl‐2, Bcl‐x, and Mcl‐1 were analyzed by immunohistochemistry. Effects of STAT3 inhibitor AG490 on NK‐YS cell line were analyzed by Western blotting and flow cytometric apoptosis assay. STAT3 was activated in six of the nine nasal NK‐cell lymphomas (67%). In contrast, STAT3 activation was detected in 35% of diffuse large B‐cell lymphoma (DLBCL) and in 10% of follicular lymphoma (FL). Frequent activation of STAT3 was significantly correlated with Mcl‐1 expression in nasal NK‐cell lymphoma, i.e., Mcl‐1 was positive in five of six STAT3‐active cases and negative in all three STAT3‐inactive ones. In DLBCL, not only six out of seven STAT3‐active cases (86%) but also eight out of thirteen STAT3‐inactive cases (62%) were positive for Mcl‐1 expression. Latent membrane protein‐1 was positive in four nasal NK‐cell lymphomas, among which three cases showed intermediate STAT3 activation. Inhibition of STAT3 activation by JAK inhibitor AG490 decreased Mcl‐1 expression and induced apoptosis in STAT3‐active NK‐YS cells. Serum starvation rather increased the Mcl‐1 level in NK‐YS cells, and this effect was also canceled by AG490. These results suggest that activation of STAT3‐Mcl‐1 axis may play a role in the chemotherapy resistance of nasal NK‐cell lymphoma. The pathway may be one of the future therapeutic targets of this intractable disease.