The Mechanism Of Cell Apoptosis Induced By Pectolinarigenin

Pectolinarigenin, active components of the medicinal plant Eupatorium odoratumL, exhibit many biological effects including apoptosis induction. However, the exact molecular mechanism of apoptosis induction is unknown. Our previous study firstly found that proapoptotic nuclear receptor family member Nur-77could translocate from the nucleus to the mitochondria and interact with Bcl-2to trigger cell apoptosis. In this study, we found that pectolinarigenin could modulate the Nur-77/bcl-2apoptotic pathway by promoting its mitochondrial targeting in cancer cells. Our results demonstrated that pectolinarigenin effectively activated jun-N-terminal kinase (JNK), which could phosphorylate Nur-77. And Nur-77phosphorylation is an essential requirement for Nur-77nuclear exporte. Inhibition of JNK activation by a jnk inhibitor could suppresse Nur-77nuclear export and cell apoptosis by pectolinarigenin. Our study found an interesting phenomenon, phosphorylation of Nur-77and activation of JNK are both dependent on the nuclear receptor RARy. Knockdown RARy by siRNA could effectively suppress the phosphorylation of Nur-77by pectolinarigenin. The cancer cell apoptotic effect of pectolinarigenin was impaired in Nur-77knockout cells and suppressed by cotreatment with leptomycin B which inhibits Nur-77cytoplasmic localization. There is a close relationship between RARy and Nur-77. Our results showed that RARy could upregulate the expression of Nur-77in different cancer cell lines and stabilize the expression of Nur-77protein. There is a direct interaction between RARy and Nur-77, which could be enhanced by pectolinarigenin.Pectolinarigenin-induced cancer cell apoptosis is also dependent on Nur-77nuclear export. We found that pectolinarigenin-induced cancer cell apoptosis was suppressed by inhibiting the nuclear output of Nur-77. And our data also showed that pectolinarigenin-induced cancer cell apoptosis was associated with a Bcl-2conformational change and Bax activation, which changed the mitochondrial membrane potential and led to the release of cytochrome C.Together, our results demonstrate that both the activation of JNK and the presence of RARy playe a key role in translocation of Nur-77from the nucleus to the cytoplasm. Our results also show that pectolinarigenin acted as a modulator of the Nur-77-mediated apoptotic pathway. Our present study provide new ideas and prospects for targeted drugs of RARy/Nur-77.