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

abstract: ...IFNB1/interferon (IFN)- 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.

...Autophagy Autophagy AUTO Autophagy 1554-8627 1554-8635 Landes Bioscience 23221969 3590251 2012AUTO0235R3 22831 10.4161/auto.22831 Basic Research Paper IFNB1/interferon--induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function Ambjrn Malene 1 Ejlerskov Patrick 1 Liu Yawei 1 Lees Michael 1 Jttel Marja 2 Issazadeh-Navikas Shohreh 1 * 1 Biotech Research and Innovation Centre (BRIC); University of Copenhagen; Copenhagen, Denmark 2 Unit for Cell Death and

... cited. IFNB1/interferon (IFN)- 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. Keywords: ATG5 ATG7 ULK1 STAT1 apoptosis cell cycle EIF4EBP1 Introduction Type I interferons (IFNs); IFNAs/IFN-s and IFNB1/IFN- and the type II IFN; IFNG/IFN-, trigger diverse biological responses in target cells, which include antiviral, immunemodulatory, antiangiogenic, antiproliferative and proapoptotic effects. 1 - 4 All type I IFNs bind a

... cells and natural killer cells, while type I IFNs can be produced by virtually all cells and are considered largely antiinflammatory. 1 Accordingly, IFNG is involved in the pathogenesis of the inflammatory disease multiple sclerosis (MS), while IFNB1 is a major therapeutic agent used to treat MS. 7 , 8 Moreover, the antiproliferative and proapoptotic responses to the different IFN species vary considerably among different cancer cell lines with IFNB1 in general being more potent than IFNAs and IFNG

... type I IFNs has not been reported previously. In the present study we report for the first time that IFNB1 can induce autophagy in breast cancer cells using several different methods that measure steady-state autophagy levels or autophagic flow. We further show that IFNB1 has antiproliferative and proapoptotic effects in MCF-7 breast cancer cells. To elucidate the biological relevance of IFNB1-induced autophagy, we silenced several core autophagy molecules by siRNAs and showed that IFNB1-induced

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Gene: IFNB1 - interferon, beta 1, fibroblast - (NCBI)

Protein : 1au1

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