Inhibition of Polo-like kinase 1 (PLK1) triggers cell apoptosis via ROS-caused mitochondrial dysfunction in colorectal carcinoma,Journal of Cancer Research and Clinical Oncology

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Inhibition of Polo-like kinase 1 (PLK1) triggers cell apoptosis via ROS-caused mitochondrial dysfunction in colorectal carcinoma
Journal of Cancer Research and Clinical Oncology ( IF 2.7 ) Pub Date : 2023-02-22 , DOI: 10.1007/s00432-023-04624-2
Ya Feng ₁ , Tianjiao Li ₁ , Zhoujun Lin ₁ , Yin Li ₁ , Xiao Han ₁ , Xiaolin Pei ₁ , Zhenkun Fu _{1,

2} , Qiao Wu ₃ , Di Shao ₄ , Chenggang Li ₁

Affiliation

Background

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers. Polo-like kinase 1 (PLK1), a member of the serine/threonine kinase PLK family, is the most investigated and essential in the regulation of cell cycle progression, including chromosome segregation, centrosome maturation and cytokinesis. However, the nonmitotic role of PLK1 in CRC is poorly understood. In this study, we explored the tumorigenic effects of PLK1 and its potential as a therapeutic target in CRC.

Methods

GEPIA database and immunohistochemistry analysis were performed to evaluate the abnormal expression of PLK1 in CRC patients. MTT assay, colony formation and transwell assay were performed to assess cell viability, colony formation ability and migration ability after inhibiting PLK1 by RNAi or the small molecule inhibitor BI6727. Cell apoptosis, mitochondrial membrane potential (MMP) and ROS levels were evaluated by flow cytometry. Bioluminescence imaging was performed to evaluate the impact of PLK1 on CRC cell survival in a preclinical model. Finally, xenograft tumor model was established to study the effect of PLK1 inhibition on tumor growth.

Results

First, immunohistochemistry analysis revealed the significant accumulation of PLK1 in patient-derived CRC tissues compared with adjacent healthy tissues. Furthermore, PLK1 inhibition genetically or pharmacologically significantly reduced cell viability, migration and colony formation, and triggered apoptosis of CRC cells. Additionally, we found that PLK1 inhibition elevated cellular reactive oxygen species (ROS) accumulation and decreased the Bcl2/Bax ratio, which led to mitochondrial dysfunction and the release of Cytochrome c, a key process in initiating cell apoptosis.

Conclusion

These data provide new insights into the pathogenesis of CRC and support the potential value of PLK1 as an appealing target for CRC treatment. Overall, the underlying mechanism of inhibiting PLK1-induced apoptosis indicates that the PLK1 inhibitor BI6727 may be a novel potential therapeutic strategy in the treatment of CRC.

中文翻译：

结直肠癌中 Polo 样激酶 1 (PLK1) 的抑制通过 ROS 引起的线粒体功能障碍触发细胞凋亡

背景

结直肠癌（CRC）是最常诊断的癌症之一。 Polo 样激酶 1 (PLK1) 是丝氨酸/苏氨酸激酶 PLK 家族的成员，在细胞周期进程（包括染色体分离、中心体成熟和胞质分裂）的调节中研究最多且至关重要。然而，人们对 PLK1 在 CRC 中的非有丝分裂作用知之甚少。在这项研究中，我们探讨了 PLK1 的致瘤作用及其作为 CRC 治疗靶点的潜力。

方法

采用GEPIA数据库和免疫组化分析评估CRC患者PLK1的异常表达情况。通过MTT实验、集落形成实验和Transwell实验评估RNAi或小分子抑制剂BI6727抑制PLK1后的细胞活力、集落形成能力和迁移能力。通过流式细胞术评估细胞凋亡、线粒体膜电位（MMP）和ROS水平。进行生物发光成像以评估临床前模型中 PLK1 对 CRC 细胞存活的影响。最后，建立异种移植肿瘤模型，研究PLK1抑制对肿瘤生长的影响。

结果

首先，免疫组织化学分析显示，与邻近的健康组织相比，患者来源的 CRC 组织中 PLK1 显着积累。此外，PLK1 的基因或药理学抑制显着降低细胞活力、迁移和集落形成，并引发 CRC 细胞凋亡。此外，我们发现 PLK1 抑制会增加细胞活性氧 (ROS) 的积累并降低 Bcl2/Bax 比率，从而导致线粒体功能障碍和细胞色素 c 的释放，这是启动细胞凋亡的关键过程。