Smac mimetic induces an early wave of gene expression via NF-κB and AP-1 and a second wave via TNFR1 signaling. (1st May 2018)

• Record Type: Journal Article
• Authors: Schmidt, Nadine; Haydn, Tinka; Schneider, Ines; Busch, Hauke; Boerries, Melanie; Fulda, Simone
• Is Part Of: Cancer letters. Volume 421(2018)
• Page Start: 170
• Page End: 185
• Publication Date: 2018-05-01
• Subjects: Smac mimetics -- Microarray -- Breast cancer -- Cell death -- IAP proteins -- Cytokines; AP-1 activator protein 1 -- BIR baculovirus IAP repeat -- cIAP cellular IAP -- DEG differential regulated gene -- FADD FAS-associated protein with death domain -- FCS fetal calf serum -- GSEA gene set enrichment analysis -- IAP Inhibitor of Apoptosis -- IFN interferon -- IKK IκB kinase -- IRF IFN regulatory factor -- IκB Inhibitor of κB -- MAPK mitogen-activated protein kinase -- NF-κB nuclear factor-kappaB -- NIK NF-κB-inducing kinase -- PC principal component -- PCA principal component analysis -- PI propidium iodide -- RING really interesting new gene -- RIPK receptor-interacting serine/threonine-protein kinase -- Smac second mitochondria-derived activator of caspases -- TNF tumor necrosis factor -- TNFR TNF receptor -- TRADD TNFR type 1-associated death domain protein -- TRAF TNF receptor-associated factor -- TRAIL TNFR-associated apoptosis-inducing ligand -- TWEAK TNF-like weak inducer of apoptosis -- UBA ubiquitin-associated -- XIAP X-linked IAP -- zVAD.fmk N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.01.082
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Smac (second mitochondria-derived activator of caspases) mimetics are considered as promising cancer therapeutics, but little is yet known about how they alter gene expression. In this study, we used an unbiased genome-wide expression array to investigate gene regulation induced by the Smac mimetic BV6 in breast cancer cell lines. Here, we discover that tumor necrosis factor (TNF)α/TNF receptor 1 (TNFR1) auto-/paracrine signaling regulates Smac mimetic-stimulated changes in gene expression in a time-dependent manner. TNFR1-independent and -dependent genes account for two subsequent waves of BV6-induced gene expression. While the first wave mostly comprises TNFR1-independent genes and involves nuclear factor-kappa B (NF-κB) and activator protein (AP)-1 transcription factors, the second wave largely depends on TNFR1 signaling. Interestingly, disrupting auto-/paracrine TNFα/TNFR1 signaling by knockdown of TNFR1 strongly attenuates the BV6-induced second wave of gene expression and upregulation of many pathways, including NF-κB, apoptosis and immune signaling, while activation of mitogen-activated protein kinase (MAPK) signaling occurs also in TNFR1 knockdown cells. Thus, BV6 alters gene expression in a time- as well as TNFR1-dependent manner. Graphical abstract: Highlights: Smac mimetic alters gene expression in two waves. The first wave primarily involves NF-κB and AP-1 transcription factors. The second wave largely depends on TNFR1 signaling. Smac mimetic stimulates MAPK signaling independently of TNFR1.