Abstract
Breast cancer prognosis is frequently good but a substantial number of patients suffer from relapse. The death receptor ligand TRAIL can in combination with Smac mimetics induce apoptosis in some luminal-like ER-positive breast cancer cell lines, such as CAMA-1, but not in MCF-7 cells. Here we show that TRAIL and the Smac mimetic LCL161 induce non-canonical NF-κB and IFN signaling in ER-positive MCF-7 cells and in CAMA-1 breast cancer cells when apoptosis is blocked by caspase inhibition. Levels of p52 are increased and STAT1 gets phosphorylated. STAT1 phosphorylation is induced by TRAIL alone in MCF-7 cells and is independent of non-canonical NF-κB since downregulation of NIK has no effect. The phosphorylation of STAT1 is a rather late event, appearing after 24 hours of TRAIL stimulation. It is preceded by an increase in IFNB1 mRNA levels and can be blocked by siRNA targeting the type I IFN receptor IFNAR1 and by inhibition of Janus kinases by Ruxolitinib. Moreover, downregulation of caspase-8, but not inhibition of caspase activity, blocks TRAIL-mediated STAT1 phosphorylation and induction of IFN-related genes. The data suggest that TRAIL-induced IFNB1 expression in MCF-7 cells is dependent on a non-apoptotic role of caspase-8 and leads to autocrine interferon-β signaling.
Highlights
Breast cancer can be grouped into different subtypes, where expression of the estrogen receptor (ER) and amplification of human epidermal growth factor receptor 2 (HER2) are important markers for selecting hormonal therapy or therapies targeting HER2 [1]
TNF-related apoptosis-inducing ligand (TRAIL) together with second mitochondrial activator of caspases (Smac) mimetics induce IFN and NF-κB signaling in breast cancer cell lines
We show that treatment of CAMA-1 and MCF-7, two ER-positive and luminal-like breast cancer cell lines, with Smac mimetic LCL161 and TRAIL induces IFN signaling with phosphorylation of signal transducer and activator of transcription 1 (STAT1)
Summary
Breast cancer can be grouped into different subtypes, where expression of the estrogen receptor (ER) and amplification of human epidermal growth factor receptor 2 (HER2) are important markers for selecting hormonal therapy or therapies targeting HER2 [1]. Based on global mRNA expression, tumors have been classified in intrinsic subtypes: luminal A and B, normal-like, basal, and HER2-enriched [2, 3]. Luminal A, B and normal-like tumors generally express ER [2, 3], with luminal A having the best prognosis [4]. HER2-enriched tumors frequently have amplification of the HER2 gene and basal-like tumors in general lack expression of both ER and progesterone receptors as well as HER2-amplification [2, 3]. Small molecules that mimic functions of second mitochondrial activator of caspases (Smac), have been developed to inhibit certain inhibitor of apoptosis proteins (IAPs), such as cellular
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