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Journal of Cancer Research and Clinical Oncology

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22-02-2023 | Colorectal Cancer | Research

Inhibition of Polo-like kinase 1 (PLK1) triggers cell apoptosis via ROS-caused mitochondrial dysfunction in colorectal carcinoma

Authors: Ya Feng, Tianjiao Li, Zhoujun Lin, Yin Li, Xiao Han, Xiaolin Pei, Zhenkun Fu, Qiao Wu, Di Shao, Chenggang Li

Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2023

Abstract

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.

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Title: Inhibition of Polo-like kinase 1 (PLK1) triggers cell apoptosis via ROS-caused mitochondrial dysfunction in colorectal carcinoma
Authors: Ya Feng
Tianjiao Li
Zhoujun Lin
Yin Li
Xiao Han
Xiaolin Pei
Zhenkun Fu
Qiao Wu
Di Shao
Chenggang Li
Publication date: 22-02-2023
Publisher: Springer Berlin Heidelberg
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Cancer Research and Clinical Oncology / Issue 10/2023
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-023-04624-2

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