Silibinin down-regulates FAT10 and modulate TNF-α/IFN-γ-induced chromosomal instability and apoptosis sensitivity.

Yun Gao,Caroline G L Lee,Way-Champ Mah,Steven Setiawan Theng

doi:10.1242/bio.011189

Abstract

ABSTRACTPleiotropic 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.

Highlights

First proposed by Virchow during the 19th century, a causal link between inflammation and various cancers, including liver, colorectal, gastric, lung, breast and cervical cancers is supported by a large number of epidemiological and experimental data (Hojilla et al, 2008; Itzkowitz and Yio, 2004; McNamara and El-Omar, 2008; Szabo et al, 2007)
The key molecules in these pathways revolved around molecules involved in inflammation (e.g. TNF, NF-κB and IFN) and cell-death/ survival (e.g. FOS, p53) suggesting FAT10 play roles in inflammation as well as cell-death/survival through TNF and NF-κB (Fig. 1G,H) which concurs with our previous observations (Ren et al, 2011)
Since FAT10 was previously reported to directly mediate the induction of chromosome instability (CIN) by TNF-α (Ren et al, 2011), we examined if silibinin can mitigate CIN in TNF-α and IFN-γ (TI) treated cells as silibinin inhibits FAT10 expression

Summary

Introduction

First proposed by Virchow during the 19th century, a causal link between inflammation and various cancers, including liver, colorectal, gastric, lung, breast and cervical cancers is supported by a large number of epidemiological and experimental data (Hojilla et al, 2008; Itzkowitz and Yio, 2004; McNamara and El-Omar, 2008; Szabo et al, 2007). Targeting molecules downstream of the NF-κB signaling pathway might be a better choice as a therapeutic target for inflammation-associated cancers as this may have lesser side effects (Yamamoto and Gaynor, 2001). Our recent study provides evidence that FAT10 is one of the downstream molecules in the pathway of inflammationinduced tumorigenesis (Gao et al, 2014) mediating the effect of TNF-α in causing numerical chromosome instability (CIN) (Gao et al, 2014; Ren et al, 2006) through its interaction with the mitotic checkpoint protein MAD2 (mitotic arrest deficient-2) (Liu et al, 1999; Theng et al, 2014) and protecting cells from TNF-α-induced cell death (Ren et al, 2011). FAT10 is an 18 kDa protein belonging to the ubiquitin-like modifier (UBL) family of proteins. FAT10 was reported to be activated by the E1-enzyme UBA6/E1-L2 (Chiu et al, 2007) and USE1 (Aichem et al, 2010)

Methods

Results

Conclusion