The NUPR1/p73 axis contributes to sorafenib resistance in hepatocellular carcinoma*
The NUPR1/p73 axis contributes to sorafenib resistance in hepatocellular carcinoma*
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DOI：
10.1016/j.canlet.2021.07.026
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发表时间：
2021-07-29
期刊：
影响因子：
9.7
通讯作者：
Cervello, Melchiorre
中科院分区：
文献类型：
--
作者：
Augello, Giuseppa;Emma, Maria Rita;Cervello, Melchiorre
多激酶抑制剂索拉非尼是FDA批准的第一种用于治疗晚期肝细胞癌（HCC）患者的药物。然而，索拉非尼耐药仍然是提高HCC治疗有效性的主要挑战。以前，我们确定了索拉非尼治疗人肝癌细胞后调节的几个基因，包括应激诱导核蛋白1（NUPR 1）基因。多项研究表明，NUPR 1调节自噬、凋亡和化疗耐药性。在这里，我们证明了索拉非尼治疗肝癌细胞导致自噬通量的激活。HCC细胞中NUPR 1敲低（KD）与p62表达增加相关，表明自噬通量受损，并与细胞对索拉非尼敏感性的显著增加相关。在NUPR 1 KD细胞中，NUPR 1水平的降低与p73及其下游转录靶点p73 A、NOXA和p21的表达增加相关。与任一基因的单一KD相比，HCC细胞中p73和NUPR 1的同时沉默导致对索拉非尼的抗性增加。相反，通过新型p73小分子激活剂NSC59984对p73的药理学激活确定了索拉非尼处理的HCC细胞中的协同抗肿瘤作用。当与单独的任一种治疗相比时，NSC59984和索拉非尼的组合在体内协同抑制HCC细胞的肿瘤生长。我们的数据表明，NUPR 1 KD实现的p73通路的激活增强了索拉非尼诱导的HCC细胞中的抗肿瘤作用。此外，p73激活剂NSC 59984和索拉非尼的联合药物治疗可能代表了肝癌治疗的一种新方法。
The multikinase inhibitor sorafenib was the first drug approved by the FDA for treating patients with advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a major challenge for improving the effectiveness of HCC treatment. Previously, we identified several genes modulated after sorafenib treatment of human HCC cells, including the stress-inducible nuclear protein 1 (NUPR1) gene. Multiple studies have shown that NUPR1 regulates autophagy, apoptosis, and chemoresistance. Here, we demonstrate that treatment of HCC cells with sorafenib resulted in the activation of autophagic flux. NUPR1 knock-down (KD) in HCC cells was associated with increased p62 expression, suggesting an impairment of autophagic flux, and with a significant increase of cell sensitivity to sorafenib. In NUPR1 KD cells, reduced levels of NUPR1 were associated with the increased expression of p73 as well as its downstream transcription targets PUMA, NOXA, and p21. Simultaneous silencing of p73 and NUPR1 in HCC cells resulted in increased resistance to sorafenib, as compared to the single KD of either gene. Conversely, pharmacological activation of p73, via the novel p73 small molecule activator NSC59984, determined synergistic anti-tumor effects in sorafenib-treated HCC cells. The combination of NSC59984 and sorafenib, when compared to either treatment alone, synergistically suppressed tumor growth of HCC cells in vivo. Our data suggest that the activation of the p73 pathway achieved by NUPR1 KD potentiates sorafenib-induced anti-tumor effects in HCC cells. Moreover, combined pharmacological therapy with the p73 activator NSC59984 and sorafenib could represent a novel approach for HCC treatment.