Abstract
Concanavalin A (ConA) is a lectin and T-cell mitogen that can activate immune responses. In recent times, ConA-induced cell death of hepatoma cells through autophagy has been reported and its therapeutic effect was confirmed in a murine in situ hepatoma model. However, the molecular mechanism of ConA-induced autophagy is still unclear. As macrophage migration inhibitory factor (MIF), which is a proinflammatory cytokine, can trigger autophagy in human hepatoma cells, the possible involvement of MIF in ConA-induced autophagy was investigated in this study. We demonstrated that cell death is followed by an increment in MIF expression and secretion in the ConA-stimulated human hepatoma cell lines, HuH-7 and Hep G2. In addition, ConA-induced autophagy and cell death of hepatoma cells were blocked in the presence of an MIF inhibitor. Knockdown of endogenous MIF by small hairpin RNA confirmed that MIF is required for both ConA-induced autophagy and death of hepatoma cells. Furthermore, signal pathway studies demonstrated that ConA induces signal transducer and activator of transcription 3 (STAT3) phosphorylation to trigger MIF upregulation, which in turn promotes Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-dependent autophagy. By using a murine in situ hepatoma model, we further demonstrated that MIF contributes to anti-hepatoma activity of ConA by regulating STAT3–MIF–BNIP3-dependent autophagy. In summary, our findings uncover a novel role of MIF in lectin-mediated anti-hepatoma activities by regulating autophagy.
Highlights
Because of the contrasting properties of autophagy concerning its effects on tumor progression and suppression, the roles of autophagy in tumorigenesis and cancer progress remain controversial
By using a murine in situ hepatoma model, we further demonstrated that migration inhibitory factor (MIF) contributes to anti-hepatoma activity of Concanavalin A (ConA) by regulating signal transducer and activator of transcription 3 (STAT3)–MIF–Bcl-2/adenovirus E1B kDa-interacting protein 3 (BNIP3)-dependent autophagy
We found that ConA has a therapeutic effect in a murine in situ hepatoma model by arousing a strong immune response against tumor growth and inducing hepatoma cell death through autophagy in vitro.[22,23,24]
Summary
Because of the contrasting properties of autophagy concerning its effects on tumor progression and suppression, the roles of autophagy in tumorigenesis and cancer progress remain controversial. Received 10.9.15; revised 29.10.15; accepted 03.11.15; Edited by GM Fimia immunomodulatory and cytotoxic activities against hepatoma cells, it has the potential to be a new anti-hepatoma therapeutic agent.[20,21] In our previous study, we found that ConA has a therapeutic effect in a murine in situ hepatoma model by arousing a strong immune response against tumor growth and inducing hepatoma cell death through autophagy in vitro.[22,23,24] the detailed mechanism of ConA-induced autophagic cell death of hepatoma cells remains unclear. Numerous studies have revealed that ConA can elicit the secretion of pro-inflammatory cytokines, including MIF.[36,37,38,39] Studies have reported that ConA can induce hepatitis in mice, and that the knockdown of MIF can protect mice against ConA-induced liver injury.[40] the involvement of MIF in ConA-induced autophagic cell death of hepatoma cells is unclear. Our results indicate that MIF is required for ConA-induced autophagic cell death of hepatoma cells and anti-tumor activities in mice
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