title: Novel role of ASC as a regulator of metastatic phenotype.
abstract: Disorders of cytoskeletal remodeling and signal transduction are frequently involved in cancer progression. In particular, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) has been reported a proapoptotic molecule that is epigenetically silenced in several human cancers. ASC is a well-characterized adaptor protein involved in the formation of multiprotein oligomers, called inflammasomes, and plays a crucial role in the activation and secretion of interleukin-1β and interleukin-18 in innate immune cells. However, the function of ASC in the regulation of tumor progression remains elusive. The present investigation examined the involvement of ASC in cancer progression and the acquisition of metastatic ability. To determine the effect of ASC depletion in in vitro and in vivo model systems, ASC was stably knocked down in B16 murine melanoma cell lines using retroviral transduction of shRNA. ASC suppression increased the motility of B16BL6 cells in scratch assays and augmented invasiveness as assessed by a Matrigel-coated transwell system. Invadopodia formation and Src phosphorylation level were markedly enhanced in ASC-knockdown cells as well. Since caspase-8 has been reported to enhance cellular migration by Tyr380 phosphorylation via Src, we examined Tyr380 phosphorylation of caspase-8 in ASC-knockdown cells and found it to be elevated in ASC-knockdown cells but attenuated by z-VAD-fmk or z-IETD-fmk. Moreover, ASC ablation increased pulmonary metastasis in mice after intravenous injection of B16BL6 cells. Our cumulative findings indicate that ASC suppresses cancer metastasis and progression via the modulation of cytoskeletal remodeling and the Src-caspase-8 signaling pathway.
authors.affiliation: Department of Molecular Oncology, Institute of Pathogenesis and Disease Prevention, Graduate School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.|Department of Dermatology, School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Nagisa
authors.initials: N
authors.lastname: Okada
authors.affiliation: Department of Molecular Oncology, Institute of Pathogenesis and Disease Prevention, Graduate School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan. chifumif@shinshu-u.ac.jp.|Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan. chifumif@shinshu-u.ac.jp.
authors.forename: Chifumi
authors.initials: C
authors.lastname: Fujii
authors.affiliation: Department of Molecular Oncology, Institute of Pathogenesis and Disease Prevention, Graduate School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Department of Molecular Oncology, Institute of Pathogenesis and Disease Prevention, Graduate School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.|Department of Surgery, School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kitazawa
authors.affiliation: Department of Dermatology, School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Okuyama
authors.affiliation: Department of Molecular Oncology, Institute of Pathogenesis and Disease Prevention, Graduate School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.|Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.|Department of Comprehensive Cancer Therapy, School of Medicine, Shinshu University, Asahi 3-1-1, Matsumoto, 390-8621, Japan.
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.affiliation: Department of Molecular and Cellular Health Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Hida
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; C498534:Pycard protein, mouse; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D053181:Caspase 8
keywords: ASC; Src signaling pathway; invadopodia; metastasis; motility