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
Related in: MedlinePlus
License 1 - License 2
Mentions: Studies show that the contradictory functions of the Jnk signal stimulated by Tnf are in part determined by the duration of Jnk activity. A short duration (<2 h) promotes survival/proliferation, whereas longer duration (>2 h) promotes cell death (Sakon et al., 2003; Liu and Lin, 2005). We found that Jnk signal duration is limited in LC compared with HSPC in response to TNF stimulation (Fig. 5 A). We predicted that extending the duration of Tnf–induced Jnk activation might convert the survival signal into death signal in LC.
Affiliation: Molecular Biology Program, Department of Biology, Loyola University Chicago, Chicago, IL 60660.