title: SOCS1 silencing enhances antitumor activity of type I IFNs by regulating apoptosis in neuroendocrine tumor cells.
abstract: IFN-alpha is commonly used for biotherapy of neuroendocrine carcinomas. However, its antitumor efficacy is often limited due to IFN resistance. In this study, we evaluate the role of suppressor of cytokine signaling protein 1 (SOCS1) in modulating the effects of type I IFNs (IFN-alpha and IFN-beta) in human neuroendocrine BON1 and CM tumor cells. In both cell lines, type I IFNs activated signal transducers and activators of transcription (STAT) and significantly decreased cell viability. However, the effects of IFN-beta were significantly more pronounced than those of IFN-alpha and involved the induction of the intrinsic apoptotic pathway as shown by cleavage of caspase-8, Bid, and caspase-9. Stable overexpression of SOCS1 completely abolished the apoptotic effects of both type I IFNs. In contrast, small interfering RNA (siRNA)-mediated silencing of SOCS1 resulted in strongly enhanced type I IFN signaling as shown by increased and prolonged STAT phosphorylation and stronger induction of apoptosis. Silencing of SOCS1 was associated with down-regulation of basal Bcl-2 and Bcl-xL and up-regulation of basal Bak and Bax, suggesting that reduced SOCS1 expression might lower the threshold of susceptibility to type I IFN-mediated apoptosis by decreasing the ratio of antiapoptotic to proapoptotic molecules. In summary, our results indicate an important role of SOCS1 in IFN resistance of neuroendocrine tumor cells, mediated through negative regulation of type I IFN-induced Jak/STAT signaling. Knocking down SOCS1 by siRNA is a promising new approach to enhance the therapeutic potency of type I IFNs in neuroendocrine tumors.
authors.affiliation: Department of Internal Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zitzmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.forename: Enrico N
authors.initials: EN
authors.lastname: De Toni
authors.forename: Sebastian
authors.initials: S
authors.lastname: Baehs
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meinecke
authors.forename: Gerald
authors.initials: G
authors.lastname: Spöttl
authors.forename: Heinrich H H D
authors.initials: HH
authors.lastname: Meyer
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Auernhammer
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D015536:Down-Regulation; D006801:Humans; D007370:Interferon Type I / Q000276:immunology / Q000494:pharmacology*; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
chemical_list: D007370:Interferon Type I; D034741:RNA, Small Interfering; C108944:SOCS1 protein, human; D050791:STAT Transcription Factors; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins