Interferon-gamma induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1)

Abstract

Interferon-gamma (IFN-γ) is a pleiotropic cytokine with immunomodulatory, anti-viral, and anti-proliferative effects. In this study, we examined the effects of IFN-γ on autophagy and cell growth in human hepatocellular carcinoma (HCC) cells. IFN-γ inhibited cell growth of Huh7 cells with non-apoptotic cell death. IFN-γ induced autophagosome formation and conversion/turnover of microtubule associated protein 1 light chain 3 (LC3) protein. Furthermore, overexpression of IRF-1 also induced autophagy in Huh7 cells. Silencing IRF-1 expression with target small hairpin RNA blocked autophagy induced by IFN-γ. Silencing of the autophagy signals Beclin-1 or Atg5 attenuated the inhibitory effect of IFN-γ on Huh7 cells with decreased cell death. Additionally, IFN-γ activated autophagy in freshly cultured human HCC cells. Together, these findings show that IFN-γ induces autophagy through IRF-1 signaling pathway and the induction of autophagy contributes to the growth-inhibitory effect of IFN-γ with cell death in human liver cancer cells.

Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy

“…5 It has been reported that when organelles and portions of the cytoplasm are degraded beyond a certain threshold, autophagic cell death is induced. 6,7 It is also possible that autophagy can kill the cells by selective degradation of essential proteins. Autophagic cell death is regulated by a molecular mechanism distinct from that of apoptosis although BECN1 and Bcl-2 can cooperate with Atg5 to regulate both autophagy and apoptosis.…”

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“…For example, IRF-1 mediates cell fate by facilitating apoptosis with or without functional p53 in breast cancer (Schwartz, Shajahan, & Clarke, 2011). More recently, it was found that overexpression of IRF-1 induces autophagy in human hepatocellular carcinoma cells together with IFN- (Li et al 2012). In addition, IRF-1 is a key transcription factor for the induction of RIG-I by 25-hydroxycholesterol, and the IRF-1/RIG-I axis mediates 25-hydroxycholesterol-induced IL-8 production in atherosclerosis (Wang, Xia, Liu, & Gu, 2012).…”

Immunotherapy for hepatocellular carcinoma: From basic research to clinical use

“…They were found to be decreased in serum of patients with HCC. All three types of interferon (IFN-α, IFN-β, IFN-γ) have been proved to be effective in inhibiting HCC by inducing tumor cell apoptosis or autophagy [12][13][14] . However, the efficiencies among different types of interferon are under debate.…”