title: 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.
authors.affiliation: Biotech Research and Innovation Centre (BRIC ), University of Copenhagen, Copenhagen, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Ambjørn
authors.forename: Patrick
authors.initials: P
authors.lastname: Ejlerskov
authors.forename: Yawei
authors.initials: Y
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Lees
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.forename: Shohreh
authors.initials: S
authors.lastname: Issazadeh-Navikas
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016899:Interferon-beta