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.

Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

“…Mcl-1 is a Bcl-2 family member that negatively regulates both apoptosis and autophagy [31,32]. This molecule has been previously reported to be reduced by AG490 treatment [33,34] and more recent studies have reported that also HSF1 can influence Mcl-1 expression [35]. However, a link between AG490, HSF1 and Mcl-1 molecules was not previously reported.…”

Resveratrol Prevents EBV Transformation and Inhibits the Outgrowth of EBV-Immortalized Human B Cells

“…The effect of resveratrol on the activation state of STAT-3 was investigated in EBV-infected B cells, since STAT-3 signal activation is implicated in the EBV-mediated oncogenesis [24], and previous studies have shown that resveratrol is an effective STAT-3 inhibitor [25], [26]. Whole-cell protein extracts were collected from EBV-infected B cells at 72 hrs after infection and assayed by Western blotting, with antibodies specific to phosphorylated STAT-3 at Tyr 705.…”

Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer

“…Although we were able to validate the importance of Elk-1 in controlling Mcl-1 expression we found that knockdown of SRF had little or no effect on basal or induced Mcl-1 expression (Supplementary Figure 2) Whether this is due to insufficient knockdown, recruitment of other co-activators in the absence of SRF or Elk-1 acting independently is yet to be determined. Although many additional transcription factor binding sites were found within the Mcl-1 promoter such as Stat-3 and NF-κB, two transcription factors that may have a role in Mcl-1 regulation in other cell types, it appears that these sites are not critical for the EGF induced regulation of Mcl-1 in these breast cancer cell lines (Boucher et al , 2000; Henson et al , 2006; Liu et al , 2003; Tsutsui et al , 2009). Furthermore, knockdown of both Stat-3 and NF-κB had no observable effect on basal or EGF induced Mcl-1 protein levels (Supplementary Figure 2A).…”