Laboratoire de Biochimie, CHU Amiens, Amiens, France.
EA4666, Université de Picardie Jules Verne, Amiens, France.
Cancer Lett. 2015 Jan 28;356(2 Pt B):971-7. doi: 10.1016/j.canlet.2014.11.014. Epub 2014 Nov 12.
Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis.
索拉非尼是治疗晚期肝细胞癌（HCC）的标准药物，HCC 是原发性肝癌最常见的形式。视网膜母细胞瘤（Rb）蛋白的功能丧失是肝致癌过程中的一个重要事件，但尚不清楚 Rb 状态是否调节 HCC 细胞对索拉非尼的反应。在这里，我们通过稳定的 RNA 干扰降低了 Rb 水平的 HCC 细胞中研究了这个问题。我们发现，与对照相比，Rb 水平降低的 HCC 细胞在接触索拉非尼后，细胞死亡诱导增加了两到三倍。用 Rb 水平降低的 HCC 细胞衍生的肿瘤异种移植物接种的 Balb/c 裸鼠接受索拉非尼治疗后，有 50%的动物的肿瘤完全消退，而接受对照细胞的小鼠肿瘤则稳定。我们发现，在接触索拉非尼后，HCC 细胞的 Rb 阴性状态促进了铁死亡的发生，铁死亡是一种氧化坏死形式。这些发现强调了 Rb 在 HCC 细胞对索拉非尼的反应和铁死亡调节中的作用。
