Dual role of apoptosis-associated speck-like protein containing a CARD (ASC) in tumorigenesis of human melanoma
SourceJournal of Investigative Dermatology, 133, 2, (2013), pp. 518-527
Article / Letter to editor
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Journal of Investigative Dermatology
SubjectN4i 1: Pathogenesis and modulation of inflammation
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-1beta secretion. However, phosphorylated IkappaB kinase (IKK)alpha/beta expression and NF-kappaB 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 IKKalpha/beta phosphorylation and inhibiting NF-kappaB activity. In metastatic melanoma, on the other hand, this inhibitory effect is diminished, and ASC induces tumorigenic pathways through enhanced NF-kappaB activity and inflammasome-mediated IL-1beta secretion.
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