IFNB1/interferon-β-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function

Abstract

IFNB1/interferon (IFN)-β belongs to the type I IFNs and exerts potent antiproliferative, proapoptotic, antiangiogenic and immunemodulatory functions. Despite the beneficial effects of IFNB1 in experimental breast cancers, clinical translation has been disappointing, possibly due to induction of survival pathways leading to treatment resistance. Defects in autophagy, a conserved cellular degradation pathway, are implicated in numerous cancer diseases. Autophagy is induced in response to cancer therapies and can contribute to treatment resistance. While the type II IFN, IFNG, which in many aspects differs significantly from type I IFNs, can induce autophagy, no such function for any type I IFN has been reported. We show here that IFNB1 induces autophagy in MCF-7, MDAMB231 and SKBR3 breast cancer cells by measuring the turnover of two autophagic markers, MAP1LC3B/LC3 and SQSTM1/p62. The induction of autophagy in MCF-7 cells occurred upstream of the negative regulator of autophagy MTORC1, and autophagosome formation was dependent on the known core autophagy molecule ATG7 and the IFNB1 signaling molecule STAT1. Using siRNA-mediated silencing of several core autophagy molecules and STAT1, we provide evidence that IFNB1 mediates its antiproliferative effects independent of autophagy, while the proapoptotic function of IFNB1 was strongly enhanced in the absence of autophagy. This suggests that autophagy induced by IFNB1 promoted survival, which might contribute to tumor resistance against IFNB1 treatment. It may therefore be clinically relevant to reconcile a role for IFNB1 in the treatment of breast cancer with concomitant inhibition of autophagy.

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

“…In contrast, we have recently reported that endoplasmic reticulum stress in hyperoxia-and IFNg-induced mouse models of BPD was associated with increased apoptotic cell death, although no data on autophagy were reported (39). In breast cancer lines, IFN-b induced autophagy upstream of MTORC1, whereas the proapoptotic function was significantly increased in the absence of autophagy (40). In such a scenario, inhibition of autophagy would be considered clinically more important.…”

Central Role of ULK1 in Type I Interferon Signaling

“…In addition, there is also evidence for IFN-dependent induction of autophagy (Ambjørn et al, 2013; Schmeisser et al, 2014). We determined whether inhibition of autophagy modulates IFN-dependent transcriptional activation.…”

Effect of beclin 1 expression on the biological behavior and chemotherapy sensitivity of cervical cancer cells

“…Dysfunction of the autophagic pathway has been implicated in various diseases, including cancer, obesity, cardiac disease, neurodegeneration, aging, infection and inflammatory diseases (17)(18)(19). However, the role of autophagy in association with cancer and tumorigenesis is complex and highly context-dependent (20). Autophagy may be involved in cell cycle regulation, apoptosis, angiogenesis and other aspects of tumor initiation and progression (21).…”