Journal
CELLULAR SIGNALLING
Volume 55, Issue -, Pages 17-25Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2018.12.004
Keywords
Signaling dynamics; IKK; Temporal control; Pathway analysis; Inflammation
Categories
Funding
- National Cancer Institute [U01CA174706, R01CA186193]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RR160005]
- American Cancer Society [RSG-18-006-01-CCE]
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Small molecule approaches targeting the nuclear factor kappa B (NF-kB) pathway, a regulator of inflammation, have thus far proven unsuccessful in the clinic in part due to the complex pleiotropic nature of this network. Downstream effects depend on multiple factors including stimulus-specific temporal patterns of NF-kB activity. Despite considerable advances, genome-level impact of changes in temporal NF-kappa B activity caused by inhibitors and their stimulus dependency remains unexplored. This study evaluates the effects of pathway inhibitors on early NF-kappa B activity and downstream gene transcription. 3T3 fibroblasts were treated with SC-514, an inhibitor targeted to the NF-kB pathway, prior to stimulation with interleukin 1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF-alpha). Stimulus induced NF-kappa B activation was quantified using immunofluorescence imaging over 90-minutes and gene expression tracked over 6-hours using mRNA TagSeq. When stimulated with IL-1 beta or TNF-alpha, significant differences (P < 0.05, two-way ANOVA), were observed in the temporal profiles of NF-kappa B activation between treated and untreated cells. Increasing numbers of differentially expressed genes (P < 0.01) were observed at higher inhibitor concentrations. Individual gene expression profiles varied in an inhibitor concentration and stimulus-dependent manner. The results in this study demonstrate small molecule inhibitors acting on pleiotropic pathway components can alter signal dynamics in a stimulus-dependent manner and affect gene response in complex ways.
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