HCC is a highly lethal malignancy with Sorafenib as the only molecularly targeted drug. The multifunctional stress-associated protein, NUPR1, plays an essential role in controlling cell growth, migration, invasion and Sorafenib resistance in HCC. We report here that NUPR1 expression is absent in healthy liver and it is progressively upregulated in HCC premalignant lesions such as hepatitis and cirrhosis with a maximum expression in HCC samples, highlighting that NUPR1 is a potential drug target for HCC. We therefore assessed in this work, ZZW-115, a strong inhibitor of NUPR1, as a promising candidate for the treatment of HCC. We validated its extraordinary antitumor effect on HCC by using two HCC cell lines, HepG2-and Hep3B, both in cell based experiments and xenografted mice. We further revealed that ZZW-115 treatment induced cell death by apoptosis and necroptosis mechanisms, with a concomitant mitochondrial metabolism failure that triggers lower ATP production. Furthermore, the ATP depletion cannot be rescued by the apoptosis inhibitor Z-VAD-FMK and/or the necrosis inhibitor Necrostatin-1, indicating that ZZW-115 induces cell death through the mitochondrial failure.

中文翻译：

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用小分子ZZW-115靶向NUPR1是治疗肝细胞癌的有效策略。

HCC是索拉非尼作为唯一的分子靶向药物，具有高度致死性。多功能应激相关蛋白NUPR1在控制肝癌的细胞生长，迁移，侵袭和索拉非尼耐药中起着至关重要的作用。我们在这里报告，在健康的肝脏中不存在NUPR1表达，并且在HCC癌前病变（例如肝炎和肝硬化）中其表达逐渐上调，并且在HCC样品中的表达最高，这突出说明NUPR1是HCC的潜在药物靶标。因此，在这项工作中，我们评估了NUPR1的强抑制剂ZZW-115作为治疗HCC的有希望的候选药物。我们通过在基于细胞的实验和异种移植小鼠中使用两种HCC细胞系HepG2和Hep3B验证了其对HCC的非凡抗肿瘤作用。我们进一步揭示，ZZW-115处理通过凋亡和坏死性坏死机制诱导细胞死亡，并伴随线粒体代谢衰竭，从而触发较低的ATP产生。此外，细胞凋亡抑制剂Z-VAD-FMK和/或坏死抑制剂Necrostatin-1无法挽救ATP的消耗，这表明ZZW-115通过线粒体衰竭诱导细胞死亡。