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

Abstract

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. First, immunohistochemistry analysis revealed the signi cant accumulation of PLK1 in patient-derived CRC tissues compared with adjacent healthy tissues. Furthermore, PLK1 inhibition genetically or pharmacologically signi cantly 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. In summary, 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.

Bipoladien A, a Sesterterpenoid Containing an Undescribed 5/8/5/7 Carbon Skeleton from Bipolaris maydis

“…The reduction of PLK1 can lead to the accumulation of ROS and mitochondrial dysfunction in cancer cells. 30 Therefore, we measured ROS levels in A549 cells and found that treatment with 6 for 24 h caused a dosedependent increase in ROS (Figure 6C,D). As elevated ROS levels can result in oxidative stress, we found that the expression of oxidative stress-related genes, including ATF4, SESN2, G-CSF, and TRIB3, was significantly increased after the treatment with 6 (Figure 7A).…”

“…As shown in Figure B, PLK1 decreased sharply after 6 -treatment, further demonstrating the antiproliferation effect of 6 . The reduction of PLK1 can lead to the accumulation of ROS and mitochondrial dysfunction in cancer cells . Therefore, we measured ROS levels in A549 cells and found that treatment with 6 for 24 h caused a dose-dependent increase in ROS (Figure C,D).…”