Inhibitors of the protein-protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line
Inhibitors of the protein-protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line
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磷酸化 p62 和 Keap1 之间蛋白质-蛋白质相互作用的抑制剂可减弱人肝细胞癌细胞系的化疗耐药性
DOI：
10.1080/10715762.2020.1732955
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发表时间：
2020
影响因子：
3.3
通讯作者：
Tadahiko Mashino
中科院分区：
文献类型：
--
作者：
Daisuke Yasuda;Tomoyuki Ohe;Kyoko Takahashi;Riyo Imamura;Hirotatsu Kojima;Takayoshi Okabe;Yoshinobu Ichimura;Masaaki Komatsu;Masayuki Yamamoto;Tetsuo Nagano;Tadahiko Mashino
对抗癌药物的耐药性一直是开发治疗方法和降低医疗成本的障碍。尽管索拉非尼用于治疗人类肝细胞癌 (HCC)，但耐药性限制了其疗效。 p62 是一种多功能蛋白，在多种 HCC 细胞系（例如 Huh-1 细胞）中过度表达。磷酸化 p62 (p-p62) 抑制 Keap1 和 Nrf2 之间的蛋白质相互作用 (PPI)，导致 Nrf2 过度激活，从而导致耐药性。我们发现了一种独特的 Nrf2 灭活剂，名为 K67，它可以抑制 Keap1 和 p-p62 之间的 PPI，并减弱 Huh-1 细胞中的索拉非尼耐药性。在此，我们通过对K67的两个苯磺酰基4位上的取代基进行修饰，设计并合成了新型的K67衍生物。尽管这些新衍生物将 Keap1-p-p62 PPI 抑制到与 K67 相当或更弱的水平，但异丙氧基衍生物比 K67 更大程度地增强了 Huh-1 细胞对索拉非尼的敏感性，而对 Huh-7 细胞（一种非耐药 HCC 细胞系）的活力没有任何影响。异丙氧基衍生物还增加了Huh-1细胞对瑞戈非尼的敏感性，这表明该衍生物有潜力用作克服基于Nrf2失活的化疗耐药性的药物。
Resistance to anticancer agents has been an obstacle to developing therapeutics and reducing medical costs. Whereas sorafenib is used for the treatment of human hepatocellular carcinoma (HCC), resistance limits its efficacy. p62, a multifunctional protein, is overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein–protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 andp-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised novel K67 derivatives by modification of the substituent at the 4-position of the two benzenesulfonyl groups of K67. Although these new derivatives inhibited the Keap1-p-p62 PPI to a level comparable to or weaker than that of K67, the isopropoxy derivative enhanced the sensitivity of Huh-1 cells to sorafenib to a greater extent than K67 without any influence on the viability of Huh-7 cells, which is a non-resistant HCC cell line. The isopropoxy derivative also increased the sensitivity of Huh-1 cells to regorafenib, which suggests that this derivative has the potential to be used as an agent to overcome chemoresistance based on Nrf2 inactivation.