RESUMO
Hepatic progenitor cells (HPCs) might be the origin of hepatocellular carcinoma. 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) (VD3) has been documented as an anticancer agent for various cancers. However, the potential effect of VD3 on the proliferation and malignant transformation of HPCs induced by aflatoxin B1 (AFB1) has not been determined. In this study, we found that AFB1 exhibited the stimulative effects on the proliferation, dedifferentiation and invasion of HPCs via activating AKT pathway but turning off Hippo pathway, which were terminated when VD3 was used in combination with AFB1. Furthermore, in AFB1-induced liver damage mouse model, VD3 also showed protective effect by reducing HPCs population. Together, these preclinical data not only provide a newly identified mechanism by which AFB1 affects HPCs but also strengthen the idea of developing VD3 as an anticancer agent.
Assuntos
Aflatoxina B1/farmacologia , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/patologia , Neoplasias Hepáticas/patologia , Células-Tronco/patologia , Vitamina D/análogos & derivados , Aciltransferases , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Desdiferenciação Celular , Proliferação de Células , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Venenos/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Vitamina D/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAPRESUMO
Mycoepoxydiene (MED) is a polyketide isolated from a marine fungus associated with mangrove forest. It has been shown that MED has many kinds of effects such as anti-cancer and anti-inflammatory activities. However, its effects on anaphylaxis are still unknown. Mast cells play a pivotal role in IgE-mediated allergic response. Aggregation of the high affinity IgE receptor (FcεRI) on the surface of mast cell activates a cascade of signaling events leading to the degranulation and cytokine production in mast cells. Our study showed that MED could significantly suppress antigen-stimulated degranulation and cytokine production in mast cells and IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Furthermore, we found that MED suppressed antigen-induced activation of Syk, and subsequently inhibited the phosphorylation of PLCγ1, Akt, and MAPKs such as extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 in mast cells. Collectively, our study demonstrates that MED can inhibit the activation of mast cells and protect mice from mast cell-mediated allergic response through inhibiting the activation of Syk. These results suggest that MED is a potential compound for developing a promising anti-anaphylaxis drug.