CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma
CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma
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CHK1 靶向脾酪氨酸激酶 (L) 进行肝细胞癌蛋白水解
DOI：
10.1172/jci61380
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Kang, Tiebang
中科院分区：
文献类型：
--
作者：
Hong, Jian;Hu, Kaishun;Kang, Tiebang
肝细胞癌（HCC）是目前最常见的恶性肿瘤之一，对化疗或放疗具有耐药性，因此寻找新的肝癌治疗靶点迫在眉睫。在这项研究中，我们发现检查点激酶1 （CHK1）经常过度表达，并与HCC患者的不良临床结局相关。我们进一步发现CHK1抑制剂GO6976能够使HCC细胞对顺铂敏感，表明CHK1可能在HCC中具有致癌功能。我们发现CHK1磷酸化肿瘤抑制因子脾酪氨酸激酶(L) (SYK[L])，并确定了Ser295的磷酸化位点。此外，CHK1磷酸化SYK(L)促进了其随后的蛋白酶体降解。在HCC细胞系中，SYK(L)的非磷酸化突变体的表达在抑制增殖、集落形成、移动性和肿瘤生长方面更有效。重要的是，在HCC患者中观察到CHK1和SYK(L)的表达水平呈强烈的负相关。总的来说，我们的数据表明，SYK(L)是肿瘤细胞中CHK1的底物，并且表明靶向CHK1/SYK(L)途径可能是治疗HCC的一种有希望的策略。
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GO6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.