title: Dual role of apoptosis-associated speck-like protein containing a CARD (ASC) in tumorigenesis of human melanoma.
abstract: Apoptosis-associated Speck-like protein containing a CARD (caspase recruitment domain) (ASC) was originally named because it triggered apoptosis in certain tumors. More recently, however, ASC was found to be a central adaptor protein of inflammasome, which mediates the secretion of protumorigenic inflammation. Here we examined the role of ASC in tumorigenesis of human melanoma. Compared with primary melanoma, ASC protein expression was generally downregulated in metastatic melanoma. Although overexpressing ASC in metastatic melanoma showed no effects on cell viability, silencing ASC with short hairpin RNA induced G1 cell cycle arrest, reduced cell viability, and suppressed tumorigenesis in metastatic melanoma. On the other hand, silencing ASC in primary melanoma reduced cell death, increased cell viability, and enhanced tumorigenesis. In primary and metastatic melanoma cells, ASC knockdown inhibited inflammasome-mediated caspase-1 activity and IL-1β secretion. However, phosphorylated IκB kinase (IKK)α/β expression and NF-κB activity were suppressed in metastatic melanoma and enhanced in primary melanoma after ASC knockdown. These findings suggest stage-dependent dual roles of ASC in tumorigenesis. ASC expression in primary melanoma inhibits tumorigenesis by reducing IKKα/β phosphorylation and inhibiting NF-κB activity. In metastatic melanoma, on the other hand, this inhibitory effect is diminished, and ASC induces tumorigenic pathways through enhanced NF-κB activity and inflammasome-mediated IL-1β secretion.
authors.affiliation: Department of Dermatology, University of Colorado Denver, School of Medicine, Aurora, Colorado, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Luo
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Dunn
authors.forename: David A
authors.initials: DA
authors.lastname: Norris
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Mayumi
authors.initials: M
authors.lastname: Fujita
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; C402202:PYCARD protein, human; D034741:RNA, Small Interfering; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator