NAD(P)H: Quinone oxidoreductase 1 overexpression in hepatocellular carcinoma potentiates apoptosis evasion through regulating stabilization of X-linked inhibitor of apoptosis protein
NAD(P)H: Quinone oxidoreductase 1 overexpression in hepatocellular carcinoma potentiates apoptosis evasion through regulating stabilization of X-linked inhibitor of apoptosis protein
复制标题
NAD(P)H：肝细胞癌中醌氧化还原酶 1 的过度表达通过调节 X 连锁凋亡蛋白抑制剂的稳定性来增强细胞凋亡逃避。
DOI：
10.1016/j.canlet.2019.02.053
复制
发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Chen, Juan
中科院分区：
文献类型：
--
作者：
Li, Wan-Yu;Zhou, Hong-Zhong;Chen, Juan
NAD(P)H：醌氧化还原酶 1 (NQO1) 是一种抗氧化酶，与人类乳腺癌、结肠癌、肺癌和肝癌的不良预后相关。然而，NQO1 促肿瘤功能的分子机制仍不清楚。本研究调查了 NQO1 在肝细胞癌 (HCC) 发展过程中的功能。我们发现NQO1在人类肝癌中频繁上调，其高表达水平与肿瘤分期和HCC患者的低生存率相关。 NQO1 功能丧失会抑制 HCC 细胞的生长，导致体外细胞凋亡增加，并抑制体内原位致瘤性。从机制上讲，HCC细胞中高水平的NQO1通过增加X连锁凋亡抑制蛋白（XIAP）在Ser 87的磷酸化来增强其蛋白稳定性。重新引入wile型XIAP和磷酸模拟突变体XIAP（S87D）可显着逆转NQO1敲除/敲除诱导的生长抑制和细胞凋亡。在原位植入肝癌的小鼠模型中，NQO1 抑制和 NQO1 抑制剂抑制肿瘤生长并诱导细胞凋亡。 NQO1 在维持 HCC 细胞增殖中发挥着重要作用，因此可能作为 HCC 治疗的潜在治疗靶点。
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme which is associated with poor prognosis in human breast, colon, lung and liver cancers. However, the molecular mechanisms underlying the pro-tumorigenic function of NQO1 remains unclear. This study investigated the function of NQO1 in the context of hepatocellular carcinoma (HCC) development. We found that NQO1 was frequently up-regulated in human liver cancer, and its high expression level was correlated with the tumor stage and low survival rate of HCC patients. Loss-of-function of NQO1 inhibited growth in HCC cells with increased apoptosis in vitro, and suppressed orthotopic tumorigenicity in vivo. Mechanistically, high level of NQO1 in HCC cells enhanced protein stability of X-linked inhibitor of apoptosis protein (XIAP) by increasing its phosphorylation at Ser 87. Reintroduction of wile type XIAP and the phospho-mimic mutants XIAP(S87D) significantly reversed NQO1 knock-down/out induced growth inhibition and apoptosis. In mouse model with orthotopically implanted hepatocarcinoma, NQO1 suppression and NQO1 inhibitor suppressed tumor growth and induced apoptosis. NQO1 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment.