Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

Abstract

Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-c is mediated by IRF-1 and IFN-c, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.

BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-53 axes in diffuse large B-cell lymphoma

“…3B). IRF1 has been shown to induce both ligand-dependent (extrinsic) and ligand-independent (intrinsic) caspase-mediated apoptosis (Stang et al, 2007). Recent studies demonstrated that IRF1 inhibits the expression of pro-survival members of the BCL2 family and induces the expression and activation of pro-apoptotic and antiproliferative gene products, including p53, p21 and CASP3 Tables S3, S4.…”

Sublytic C5b-9 Complexes Induce Apoptosis of Glomerular Mesangial Cells in Rats with Thy-1 Nephritis through Role of Interferon Regulatory Factor-1-dependent Caspase 8 Activation

“…Thy-1N-Of the co-up-regulated genes, IRF-1 was selected to further study its function because several experiments have reported that IRF-1 is associated with tumor cell apoptosis (20,22). Thus, IRF-1 expression levels both in the GMC attacked by sublytic C5b-9 and in the renal tissues of Thy-1N rats were determined.…”

“…These profiles were then compared with the gene expression profiles in the renal tissue of Thy-1N rats (in vivo). Among the characterized genes, we further focused on exploring the role of interferon regulatory factor-1 (IRF-1), including its effects on the caspase pathway because IRF-1 was a cell apoptosis-related gene in other reports (22)(23)(24).…”

GAMBARAN HISTOPATOLOGI EKSPRESI INTERFERON GAMMA (IFNγ) PADA FIBROADENOMA MAMMAE (FAM) DAN INVASIVE NO SPECIAL TYPE (NST) BREAST CARCINOMA

“…24,25 Kemampuan Interferon γ untuk menghambat pertumbuhan beberapa sel tumor, termasuk sel-sel tumor payudara, telah dibuktikan dalam berbagai studi. Pada beberapa literatur dikatakan bahwa Interferon γ mengobati berbagai macam tumor dengan memperantarai efek anti proliferasi epitel tumor dan sel tumor payudara (Tunon et al, 2007;Stang et al, 2007;Hong et al, 2013). Penulis lain berpendapat bahwa pada selsel epitel payudara, efek anti proliferasi Interferon γ terjadi melalui upregulasi anggota keluarga molekul apoptosis lewat penekanan ekspresi bcl-2 (Tunon et al, 2007).…”