Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis.
Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis.
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DOI：
10.1016/j.redox.2021.102122
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Du J
中科院分区：
文献类型：
--
作者：
Ren X;Li Y;Zhou Y;Hu W;Yang C;Jing Q;Zhou C;Wang X;Hu J;Wang L;Yang J;Wang H;Xu H;Li H;Tong X;Wang Y;Du J
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。尽管近年来HCC的临床治疗取得了进展，但患者的总体预后仍然很差。因此，开发一种毒性更小、更有效的治疗策略势在必行。目前，一系列的细胞、分子和药理学实验方法被用来解决双硫仑（DSF）未被认识的特性，追求将DSF重新用于癌症治疗的目标。我们发现DSF/Cu选择性地对HCC细胞系发挥有效的细胞毒作用，并有效地抑制HCC细胞的迁移、侵袭和血管生成。重要的是，我们证实了DSF/Cu可以强烈地破坏线粒体稳态，增加游离铁池，增强脂质过氧化，最终导致铁致细胞死亡。值得注意的是，NRF2的代偿性升高伴随着铁下沉的过程，并有助于对DSF/Cu的抵抗。从机制上，我们发现DSF/Cu显著激活p62的磷酸化，促进Keap1的竞争性结合，从而延长NRF2的半衰期。值得注意的是，通过RNA干扰或药物抑制剂抑制NRF2表达可显著促进脂质过氧化的积累，并使HCC细胞对DSF/Cu诱导的铁凋亡更敏感。相反，培养NRF2表达能够改善DSF/Cu激活的细胞死亡。此外，DSF/Cu可以通过同时抑制NRF2和MAPK激酶的信号通路，增强索拉非尼的细胞毒性，并在体外和体内抑制肿瘤的生长。综上所述，这些结果提供了实验证据，表明抑制代偿性NRF2升高使HCC细胞更容易受到DSF/Cu诱导的铁凋亡，这促进了DSF/Cu和索拉非尼的协同细胞毒性。
Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC, the general prognosis of patients remains poor. Therefore, it is imperative to develop a less toxic and more effective therapeutic strategy. Currently, series of cellular, molecular, and pharmacological experimental approaches were utilized to address the unrecognized characteristics of disulfiram (DSF), pursuing the goal of repurposing DSF for cancer therapy. We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells. Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death. Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu. Mechanically, we found that DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2. Notably, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis. Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu. Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo, by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase. In summary, these results provide experimental evidence that inhibition of the compensatory NRF2 elevation strengthens HCC cells more vulnerable to DSF/Cu induced ferroptosis, which facilitates the synergistic cytotoxicity of DSF/Cu and sorafenib.
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