Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma.
Inhibition of Polo-like kinase 4 induces mitotic defects and DNA damage in diffuse large B-cell lymphoma.
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抑制 Polo 样激酶 4 可诱导弥漫性大 B 细胞淋巴瘤有丝分裂缺陷和 DNA 损伤
DOI：
10.1038/s41419-021-03919-x
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发表时间：
2021-06-23
影响因子：
9
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Zhao Y;Yang J;Liu J;Cai Y;Han Y;Hu S;Ren S;Zhou X;Wang X
Polo-like kinase4(Plk4)是中心粒生物发生的关键调节因子，最近被证明在肿瘤发生中发挥关键作用。通过干扰或靶向药物阻断Plk4的表达在提高化疗疗效方面显示出诱人的潜力。然而，Plk4在弥漫性大B细胞淋巴瘤(DLBCL)中的作用尚未明确。在这项研究中，我们发现Plk4是治疗DLBCL的潜在靶点，并证明了Plk4抑制剂与阿霉素联合使用时的疗效。CFI-400945药物抑制Plk4抑制DLBCL细胞增殖，诱导细胞凋亡。抗肿瘤作用伴随着有丝分裂缺陷，包括多倍体和胞质分裂失败。P53和HIPPO/YAP肿瘤抑制信号通路的激活被认为是推动CFI-400945活性的潜在机制。此外，CFI-400945处理可引起DNA损伤反应的激活。CFI-400945联合阿霉素显著延缓了DLBCL异种移植瘤的进展。在原代DLBCL组织和细胞系中，Plk4表达增强。在接受基于CHOP的治疗的患者中，Plk4的高水平表达与较差的存活率相关，暗示Plk4是DLBCL化疗敏感性的预测生物标志物。这些结果提供了CFI-400945作为单一疗法或与阿霉素联合治疗DLBCL的治疗潜力。
Polo-like kinase 4 (PLK4), a key regulator of centriole biogenesis, has recently been shown to play key roles in tumorigenesis. Blocking PLK4 expression by interference or targeted drugs exhibits attractive potential in improving the efficacy of chemotherapy. Nevertheless, the role of PLK4 in diffuse large B-cell lymphoma (DLBCL) is still undefined. In this study, we discover that PLK4 is a potential target for the treatment of DLBCL, and demonstrate the efficacy of a PLK4 inhibitor when used in combination with doxorubicin. Pharmaceutical inhibition of PLK4 with CFI-400945 inhibited DLBCL cell proliferation and induced apoptotic cell death. The anti-tumor effects were accompanied by mitotic defects, including polyploidy and cytokinesis failure. Activation of p53 and Hippo/YAP tumor suppressor signaling pathway was identified as the potential mechanisms driving CFI-400945 activity. Moreover, CFI-400945 treatment resulted in activation of DNA damage response. Combining CFI-400945 with doxorubicin markedly delayed tumor progression in DLBCL xenografts. Finally, PLK4 was increased in primary DLBCL tissues and cell lines. High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.
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影响因子：
50.3
作者：
Parvin, Salma;Ramirez-Labrada, Ariel;Lossos, Izidore S.
通讯作者：
Lossos, Izidore S.
DOI：
10.1073/pnas.1719760115
发表时间：
2018-02-20
影响因子：
11.1
作者：
Kawakami, Masanori;Mustachio, Lisa Maria;Dmitrovsky, Ethan
通讯作者：
Dmitrovsky, Ethan
DOI：
10.1083/jcb.201606077
发表时间：
2017-11-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bury L;Coelho PA;Simeone A;Ferries S;Eyers CE;Eyers PA;Zernicka-Goetz M;Glover DM
通讯作者：
Glover DM
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Ward, Elizabeth
通讯作者：
Ward, Elizabeth
影响因子：
50.3
作者：
Mason, Jacqueline M.;Lin, Dan Chi-Chia;Mak, Tak W.
通讯作者：
Mak, Tak W.