title: Silibinin down-regulates FAT10 and modulate TNF-α/IFN-γ-induced chromosomal instability and apoptosis sensitivity.
abstract: Pleiotropic pro-inflammatory cytokines, TNF-α and IFN-γ (TI), play important yet diverse roles in cell survival, proliferation, and death. Recent evidence highlights FAT10 as a downstream molecule in the pathway of inflammation-induced tumorigenesis through mediating the effect of cytokines in causing numerical CIN and protecting cells from cytokines-induced cell death. cDNA microarray analysis of cells treated with TI revealed 493 deregulated genes with FAT10 being the most up-regulated (85.7-fold) gene and NF-κB being the key nodal hub of TI-response genes. Silibinin is reported to be a powerful antioxidant and has anti-C effects against various carcinomas by affecting various signaling molecules/pathways including MAPK, NF-κB and STATs. As NF-κB signaling pathway is a major mediator of the tumor-promoting activities of TI, we thus examine the effects of silibinin on TI-induced FAT10 expression and CIN. Our data showed that silibinin inhibited expression of FAT10, TI-induced chromosome instability (CIN) as well as sensitizes cells to TI-induced apoptosis. Significantly, silibinin suppressed intra-tumorally injected TNF-α-induced tumor growth. This represents the first report associating silibinin with FAT10 and demonstrating that silibinin can modulate TI-induced CIN, apoptosis sensitivity and suppressing TNF-α-induced tumor growth.
authors.affiliation: Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 169610, Singapore bchleec@nus.edu.sg yugao2000@hotmail.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.affiliation: NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, 119077, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore.
authors.forename: Steven Setiawan
authors.initials: SS
authors.lastname: Theng
authors.affiliation: Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 169610, Singapore NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, 119077, Singapore.
authors.forename: Way-Champ
authors.initials: WC
authors.lastname: Mah
authors.affiliation: Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 169610, Singapore NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, 119077, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore Duke-NUS Graduate Medical School Singapore, 169547, Singapore bchleec@nus.edu.sg yugao2000@hotmail.com.
authors.forename: Caroline G L
authors.initials: CG
authors.lastname: Lee
keywords: Apoptosis; Chromosomal instability; FAT10; IFN-γ; Silibinin; TNF-α