BV6 induces an early wave of gene expression via NF-B and AP-1 and a second wave via TNF/TNFR1 signaling

Smac 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 Smac mimetic BV6-induced gene regulation in breast cancer cell lines. Kinetic analysis revealed that BV6 alters gene expression in two waves. The first wave primarily involves NF-B- and AP-1 families of transcription factors, while the second wave largely depends on tumor necrosis factor receptor 1 (TNFR1) signaling. Interestingly, disrupting auto-/paracrine tumor necrosis factor- (TNF)/ (TNFR1) signaling by knockdown of TNFR1 strongly attenuates the BV6-induced second wave of gene expression and upregulation of many pathways including NF-B signaling, apoptosis and immune signalling, but not MAPK signaling pathways. Consistently, BV6 stimulates phosphorylation of cJun, a marker of MAPK cascade activation, irrespective of the presence or absence of the TNF blocking antibody Enbrel. We show here in a comprehensive overview that BV6-induced gene expression in breast cancer cells takes place in a time- as well as TNFR1-dependent manner.

48

Schmidt N, Haydn T, Schneider I, Busch H, Boerries M, Fulda S