Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition.
Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition.
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DOI：
10.3390/cancers14071714
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发表时间：
2022-03-28
期刊：
影响因子：
5.2
通讯作者：
Gu X
中科院分区：
文献类型：
--
作者：
Xie G;Zhu A;Gu X
肝细胞癌（HCC）是原发性肝癌中最常见的类型。HCC具有> 95%的令人沮丧的五年死亡率估计，在全球范围内排名为癌症相关死亡率的第四大原因。尽管最近在用多激酶抑制剂、免疫疗法和抗血管生成单克隆抗体以及其他新兴疗法治疗HCC方面取得了进展，但患者之间的疗效不同，使得HCC成为开发新型靶向治疗剂的高度优先事项。CDK 7已被开发为HCC的治疗靶点。在本研究中，我们证明了HCC细胞对THZ 1（一种选择性共价CDK 7抑制剂）高度敏感。我们进一步发现，转录因子MYC促进的细胞增殖使癌细胞对THZ 1治疗的凋亡性细胞死亡高度敏感。我们的研究结果表明，用THZ 1靶向CDK 7可能是治疗HCC的一种新的合理策略，其中MYC在细胞增殖和肿瘤生长中起着至关重要的作用。肝细胞癌（HCC）是一种致死性恶性肿瘤，死亡率高.细胞周期蛋白依赖性激酶7（CDK 7）活性的抑制在HCC中显示出治疗效果。然而，潜在的分子机制仍然难以捉摸。在这里，我们发现三种HCC细胞系HepG 2，Hep 3B和SK-Hep-1对CDK 7抑制剂THZ 1高度敏感。在小鼠模型中，THZ 1有效地降低了HepG 2肿瘤的生长和肿瘤重量。THZ 1在HepG 2中阻滞细胞周期并触发MYC相关的凋亡。为了评估MYC蛋白水平如何影响THZ 1诱导的凋亡性细胞死亡，我们在HepG 2中过表达MYC，发现外源性过表达的MYC促进细胞周期进展并增加S期细胞。THZ 1可显著诱导MYC高表达的HepG 2细胞发生S期和G2/M期凋亡。重要的是，转录抑制诱导的细胞凋亡与DNA损伤相关，外源性MYC表达进一步增强了MYC过表达HepG 2细胞中THZ 1诱导的DNA损伤反应。一致地，在HepG 2异种移植物中，THZ 1处理与DNA损伤诱导的细胞死亡相关。总之，我们的数据表明，MYC促进细胞周期进展和THZ 1抑制CDK 7的聚合效应赋予HCC对DNA损伤诱导的细胞死亡的超敏性。我们的研究结果可能为THZ 1治疗肝癌提供了一种新的策略。
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC has a dismal five-year mortality estimate of >95%, ranking as the fourth leading cause of cancer-related mortality worldwide. Despite the recent progression in the treatment of HCC with multikinase inhibitors, immunotherapy, and antiangiogenic monoclonal antibodies, among other newly emerging therapeutics, the efficacy has varied among patients, making HCC a high priority for developing novel targeted therapeutic agents. CDK7 has been exploited as a therapeutic target in HCC. In the present study, we demonstrated that HCC cells were highly susceptible to THZ1, a selective covalent CDK7 inhibitor. We further discovered that transcription factor MYC-promoted cell proliferation renders cancer cells hypersensitive to apoptotic cell death with THZ1 treatment. Our findings indicate that targeting CDK7 with THZ1 may be a new plausible strategy for treating HCC, in which MYC plays crucial roles in cell proliferation and tumor growth. Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality. The inhibition of cyclin-dependent kinase 7 (CDK7) activity has shown therapeutic efficacy in HCC. However, the underlying molecular mechanisms remain elusive. Here, we show that three HCC lines, HepG2, Hep3B, and SK-Hep-1, were highly susceptible to the CDK7 inhibitor THZ1. In mouse models, THZ1 effectively reduced HepG2 tumor growth and tumor weight. THZ1 arrested cell cycle and triggered MYC-related apoptosis in HepG2. To evaluate how MYC protein levels affected THZ1-induced apoptotic cell death, we overexpressed MYC in HepG2 and found that exogenously overexpressed MYC promoted cell cycle progression and increased cells in the S phase. THZ1 drastically engendered the apoptosis of MYC-overexpressing HepG2 cells in the S and G2/M phases. Importantly, transcription-inhibition-induced apoptosis is associated with DNA damage, and exogenous MYC expression further enhanced the THZ1-induced DNA damage response in MYC-overexpressing HepG2 cells. Consistently, in the HepG2 xenografts, THZ1 treatment was associated with DNA-damage-induced cell death. Together, our data indicate that the converged effect of MYC-promoted cell cycle progression and CDK7 inhibition by THZ1 confers the hypersensitivity of HCC to DNA-damage-induced cell death. Our findings may suggest a new therapeutic strategy of THZ1 against HCC.
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影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
64.5
作者：
FISHER, RP;MORGAN, DO
通讯作者：
MORGAN, DO
影响因子：
8
作者：
Antignani, A.;Segal, D.;FitzGerald, D. J.
通讯作者：
FitzGerald, D. J.
影响因子：
64.5
作者：
FISHER, RP;JIN, P;MORGAN, DO
通讯作者：
MORGAN, DO
影响因子：
--
作者：
Li GQ;Guo WZ;Zhang Y;Seng JJ;Zhang HP;Ma XX;Zhang G;Li J;Yan B;Tang HW;Li SS;Wang LD;Zhang SJ
通讯作者：
Zhang SJ