Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML.
Bottom Line: We determined that TNF stimulation drives the JNK-AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC.We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF-JNK-AP1 signaling pathway.Our data suggest that co-inhibition of both TNF-JNK-AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.
Affiliation: Molecular Biology Program, Department of Biology, Loyola University Chicago, Chicago, IL 60660.Show MeSH
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Mentions: Previous reports showed that NF-κB activity is significantly increased in LC and LSC (Guzman et al., 2001). We confirmed such elevated NF-κB activity in our murine LC compared with HSPC (unpublished data). In addition, we found that NF-κB activity in LC is cytokine-dependent. p65 (NF-κB) activity was turned off when LCs were incubated in a cytokine-free medium and was restored upon Tnf stimulation as measured by both nuclear localization (Fig. 3 A) and p65 phosphorylation (Fig. 3 B). We also found that all hematopoietic cytokines used in our cultures induced NF-κB activity in LC while only Tnf stimulated NF-κB in HSPC, suggesting how NF-κB activity can be elevated in subtypes of LC which do not express TNF (Fig. 3 C). Consistent with a previous report (Guzman et al., 2001), our murine LCs are more sensitive to NF-κB inhibition by BAY11-7085 (a reversible small molecule inhibitor of IκBα phosphorylation, BAY hereafter) in vitro as shown by a reduction in CFU (Fig. 3 D) and an increase in cell death (Fig. 3 E) when compared with HSPC.
Affiliation: Molecular Biology Program, Department of Biology, Loyola University Chicago, Chicago, IL 60660.