Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.
Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Histopathology and Immunohistochemistry Laboratory, Palermo, Italy.
Int J Cancer. 2019 May 15;144(10):2613-2624. doi: 10.1002/ijc.31963. Epub 2018 Dec 24.
Hepatocellular carcinoma (HCC) is a highly malignant tumor that responds very poorly to existing therapies, most probably due to its extraordinary inter- and intra-tumor molecular heterogeneity. The modest therapeutic response to molecular targeted agents underlines the need for new therapeutic approaches for HCC. In our study, we took advantage of well-characterized human HCC cell lines, differing in transcriptomic subtypes, DNA mutation and amplification alterations, reflecting the heterogeneity of primary HCCs, to provide a preclinical evaluation of the specific heat shock protein 90 (HSP90) inhibitor AUY922 (luminespib). Indeed, HSP90 is highly expressed in different tumor types, but its role in hepatocarcinogenesis remains unclear. Here, we analyzed HSP90 expression in primary human HCC tissues and evaluated the antitumor effects of AUY922 in vitro as well as in vivo. HSP90 expression was significantly higher in HCC tissues than in cirrhotic peritumoral liver tissues. AUY922 treatment reduced the cell proliferation and viability of HCC cells in a dose-dependent manner, but did not do so for normal human primary hepatocytes. AUY922 treatment led to the upregulation of HSP70 and the simultaneous depletion of HSP90 client proteins. In addition, in a cell type-dependent manner, treatment induced either both caspase-dependent β-catenin cleavage and the upregulation of p53, or Mcl-1 expression, or NUPR1 expression, which contributed to the increased efficacy of, or resistance to, treatment. Finally, in vivo AUY922 inhibited tumor growth in a xenograft model. In conclusion, HSP90 is a promising therapeutic target in HCC, and AUY922 could be a drug candidate for its treatment.
肝细胞癌（HCC）是一种高度恶性的肿瘤，对现有疗法的反应非常差，这很可能是由于其非凡的肿瘤内和肿瘤间分子异质性。分子靶向药物的治疗反应有限，突显了 HCC 需要新的治疗方法。在我们的研究中，我们利用了具有不同转录组亚型、DNA 突变和扩增改变的人 HCC 细胞系，这些改变反映了原发性 HCC 的异质性，为 HSP90 抑制剂 AUY922（luminespib）的临床前评估提供了依据。事实上，HSP90 在不同的肿瘤类型中高度表达，但它在肝癌发生中的作用仍不清楚。在这里，我们分析了原发性人 HCC 组织中 HSP90 的表达，并评估了 AUY922 在体外和体内的抗肿瘤作用。HSP90 的表达在 HCC 组织中明显高于肝硬化旁肝组织。AUY922 治疗以剂量依赖性方式降低 HCC 细胞的增殖和活力，但对正常的人原代肝细胞没有作用。AUY922 治疗导致 HSP70 的上调和 HSP90 客户蛋白的同时耗竭。此外，以细胞类型依赖性方式，治疗诱导 caspase 依赖性β-catenin 切割和 p53 的上调，或 Mcl-1 表达，或 NUPR1 表达，这有助于增加治疗的疗效或耐药性。最后，体内 AUY922 抑制了异种移植模型中的肿瘤生长。总之，HSP90 是 HCC 有前途的治疗靶点，AUY922 可能是其治疗的候选药物。
