Nrf2/HO-1信号通路对去势抵抗性前列腺癌细胞铁死亡的调控作用及机制研究

The prognosis of castration resistant prostate cancer (CRPC) is poor. Meanwhile most studies in the field are limited to apoptosis, which is progressing rather slowly. As of May 2012, Cell reports that ferroptosis is a new form of regulated cell death characterized by iron-dependent lipid peroxidation, which can be triggered by erastin. Nrf2/HO-1 signal pathway is a key regulator of the antioxidant response. Our previous study confirmed that erastin induced ferroptosis in CRPC cells, companied with increased levels of expression of Nrf2/HO-1 and lipid peroxidation. Meanwhile, knockdown of Nrf2 enhanced erastin-induced ferroptosis in CRPC cells. Therefore, we assume that activation of Nrf2/HO-1 pathway protects against ferroptosis in CRPC cells by inhibiting iron-dependent ROS and lipid peroxidation of membrane phospholipids. Further research is needed to reveal the role and mechanism of Nrf2/HO-1 on erastin-induced ferroptosis, elucidate the full path from oxidative stress to structural damage, finally provide evidence for the selection of promising targets.

目前去势抵抗性前列腺癌（CRPC）治疗效果不佳，相关研究多集中于凋亡领域且举步维艰。2012年《Cell》刊文报道化合物erastin能够诱导多种肿瘤细胞发生以铁依赖的脂质过氧化为特征的细胞死亡，即铁死亡，而Nrf2/HO-1是调控细胞内氧化应激的关键通路。本课题组前期研究证实，erastin能够诱导CRPC细胞铁死亡，该过程中Nrf2和HO-1表达上调、脂质过氧化水平增加，而沉默Nrf2使erastin诱导CRPC细胞铁死亡的作用显著增强。因此我们推测：Nrf2/HO-1信号通路通过下调细胞内铁依赖的ROS水平及膜磷脂过氧化抑制CRPC细胞铁死亡。为证实该假说，本研究拟利用erastin诱导CRPC细胞铁死亡模型和裸鼠荷瘤模型，在Nrf2/HO-1表达变化中揭示Nrf2/HO-1在CRPC细胞铁死亡中的作用及机制，阐明从氧化应激到结构损伤的完整路径，为CRPC的治疗提供新的策略和靶点。

目前去势抵抗性前列腺癌（CRPC）治疗效果不佳，相关研究多集中于凋亡领域，而凋亡抵抗限制了该领域的进展，提示需要探究新的细胞死亡方式。本课题组研究证实，erastin能够诱导CRPC细胞铁死亡，该过程中Nrf2和HO-1表达上调、脂质过氧化水平增加，而沉默Nrf2使erastin诱导CRPC细胞铁死亡的作用显著增强。沉默Nrf2/HO-1基因，增加CRPC细胞对erastin敏感性；沉默Nrf2/HO-1基因，CRPC细胞铁死亡过程中细胞内ROS水平、脂质过氧化水平进一步升高；沉默Nrf2基因，erastin诱导CRPC细胞铁死亡过程能够被HO-1诱导剂CoPP逆转。本研究进一步利用erastin诱导CRPC细胞铁死亡的裸鼠荷瘤模型，在Nrf2/HO-1表达变化中揭示Nrf2/HO-1在CRPC细胞铁死亡中的作用及机制，初步阐明Nrf2/HO-1信号通路通过下调细胞内铁依赖的ROS水平及脂质过氧化抑制CRPC细胞铁死亡，为CRPC的治疗提供新的策略和靶点。