Hepatitis B Virus Surface Antigen Enhances the Sensitivity of Hepatocytes to Fas-Mediated Apoptosis via Suppression of AKT Phosphorylation

Abstract

The Fas receptor/ligand system plays a prominent role in hepatic apoptosis and hepatocyte death. Although hepatitis B virus (HBV) surface Ag (HBsAg) is the most abundant HBV protein in the liver and peripheral blood of patients with chronic HBV infection, its role in Fas-mediated hepatocyte apoptosis has not been disclosed. In this study, we report that HBsAg sensitizes HepG2 cells to agonistic anti-Fas Ab CH11-induced apoptosis through increasing the formation of SDS-stable Fas aggregation and procaspase-8 cleavage but decreasing both the expression of cellular FLIP and the recruitment of FLIP at the death-inducing signaling complex (DISC). Notably, HBsAg increased endoplasmic reticulum stress and consequently reduced AKT phosphorylation by deactivation of phosphoinositide-dependent kinase-1 (PDPK1) and mechanistic target of rapamycin complex 2 (mTORC2), leading to enhancement of Fas-mediated apoptosis. In a mouse model, expression of HBsAg in mice injected with recombinant adenovirus-associated virus 8 aggravated Jo2-induced acute liver failure, which could be effectively attenuated by the AKT activator SC79. Based on these results, it is concluded that HBsAg predisposes hepatocytes to Fas-mediated apoptosis and mice to acute liver failure via suppression of AKT prosurviving activity, suggesting that interventions directed at enhancing the activation or functional activity of AKT may be of therapeutic value in Fas-mediated progressive liver cell injury and liver diseases.

Qingjie Fuzheng granules inhibit colorectal cancer cell growth by the PI3K/AKT and ERK pathways

“…In this pathway, death signals are transmitted via cell surface receptors that communicate with the FasL/Fas signaling pathway, which is part of the death receptor pathway. After binding to FasL, Fas trimerizes and interacts with Fas-associated protein with a death domain, which contributes to the cleavage of caspase-8 and caspase-10 and leads to activation of downstream effector caspases, including caspase-3, caspase-6 and caspase-7, ultimately causing apoptosis[24]. In this study, we demonstrated that QFGs treatment upregulated FasL and Fas protein expression.…”

“…In a previous study, overexpression of this complex has been found to induce cell proliferation, whereas p21 inhibited the effect of the cyclin D1/CDK4 complex[14]. During the regulation of cell apoptosis, Bax and Bcl-2 regulate the mitochondria-dependent pathway[21], while Fas and FasL activate the death receptor-mediated pathway[24]. We found that QFGs can inhibit proliferation via arrest of the cell cycle in HCT-116 and HCT-8 cells.…”

“…The G1/S process is highly regulated by cyclin D1, which forms complexes with CDK4[21,22]. Overexpression of the cyclin D1/CDK4 complex can enhance cell proliferation, whereas p21 can bind to this complex and inhibit its activity[24]. Therefore, the expression of CDK4, cyclin D1 and p21 indicate the proliferation state of HCT-116 and HCT-8 cells to some extent.…”

“…Once the death receptor pathway is successfully activated, the Fas-associated death domain and caspase-8 will accumulate, and caspase-8 will be cleaved. Then, caspase-8 cleaves caspase-3, which generates the activated form of caspase-3 that serves as the ultimate activator of apoptosis[24]. Therefore, one of the key approaches in the development of antitumor drugs is to promote apoptosis and inhibit tumor cell proliferation, two processes that typically promote cancer growth.…”

Contribution of glutaredoxin-1 to Fas s-glutathionylation in ethanol-induced liver injury

“…Fas-induced apoptosis has been proposed to function in various liver diseases, such as ischemia/reperfusion injury, viral hepatitis, fulminant hepatic liver failure, and nonalcoholic and alcoholic steatohepatitis [34,35,36,37]. Previous research suggested that s-glutathionylation of Fas results in robust Fas activation, which activates FasL-induced signaling and apoptosis [16,38].…”