Frequent STAT3 activation is associated with Mcl-1 expression in nasal NK-cell lymphoma.

Abstract

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.

• Authors: M Tsutsui, H Yasuda, H Suto, H Imai, Y Isobe, M Sasaki, Y Kojima, K Oshimi, K Sugimoto
• Journal: International journal of laboratory hematology (Int J Lab Hematol) Vol. 32 Issue 4 Pg. 419-26 (Aug 01 2010) ISSN: 1751-553X [Electronic] England
• PMID: 19968719 (Publication Type: Journal Article)

Chemical References

• Anticarcinogenic Agents
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• STAT3 Transcription Factor
• STAT3 protein, human
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide

Topics

• Anticarcinogenic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Flow Cytometry
• Humans
• Immunohistochemistry
• Lymphoma, Extranodal NK-T-Cell (drug therapy, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Tyrphostins (pharmacology)