PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence

Abstract

Background Identification of novel molecular target(s) is important for designing newer mechanistically driven approaches for the treatment of prostate cancer (PCa), which is one of the main causes of morbidity and mortality in men. In this study, we determined the role of polo‐like kinase 4 (PLK4), which regulates centriole duplication and centrosome amplification (CA), in PCa. Materials and Methods Employing human PCa tissue microarrays, we assessed the prevalence of CA, correlated with Gleason score, and estimated major causes of CA in PCa (cell doubling vs. centriole overduplication) by staining for mother/mature centrioles. We also assessed PLK4 expression and correlated it with CA in human PCa tissues and cell lines. Further, we determined the effects of PLK4 inhibition in human PCa cells. Results Compared to benign prostate, human PCa demonstrated significantly higher CA, which was also positively correlated with the Gleason score. Further, most cases of CA were found to arise by centriole overduplication rather than cell doubling events (e.g., cytokinesis failure) in PCa. In addition, PLK4 was overexpressed in human PCa cell lines and tumors. Moreover, PLK4 inhibitors CFI‐400945 and centrinone‐B inhibited cell growth, viability, and colony formation of both androgen‐responsive and androgen‐independent PCa cell lines. PLK4 inhibition also induced cell cycle arrest and senescence in human PCa cells. Conclusions CA is prevalent in PCa and arises predominantly by centriole overduplication as opposed to cell doubling events. Loss of centrioles is cellular stress that can promote senescence and suggests that PLK4 inhibition may be a viable therapeutic strategy in PCa.

Aberrant expression of polo‑like kinase 4 in renal cell carcinoma: Association with clinicopathological characteristics and long‑term survival

“…----------------------------------------------------- A previous study indicated that both DFS and OS rates were reduced in patients with non-small cell lung cancer with high PLK4 expression compared with patients with low PLK4 expression (14). Similarly, the present study revealed that high PLK4 expression was partially associated with poor survival in patients with RCC, which could be explained by PLK4 facilitating excessive centrosome amplification (15). The latter could induce the metastatic potential and invasion of tumor cells, which in turn may result in poor survival of patients with RCC (34).…”

“…PLK4 is located on human chromosome 4q27-28 and has been reported to modulate centriole duplication, which affects cancer invasion and metastasis (25). Previous studies have detected its expression in various solid tumors, including those of the bladder and prostate (15,18). For example, a previous study has demonstrated elevated PLK4 expression in human prostate cancer cell lines and tumor tissues derived from patients with prostate cancer (15).…”

“…Previous studies have detected its expression in various solid tumors, including those of the bladder and prostate (15,18). For example, a previous study has demonstrated elevated PLK4 expression in human prostate cancer cell lines and tumor tissues derived from patients with prostate cancer (15). It has also been reported that PLK4 expression is upregulated in bladder cancer tissues compared with in normal bladder tissues (18).…”

“…Polo-like kinase 4 (PLK4), also referred to as serum-inducible-kinase akin kinase, is a type of serine/threonine-protein kinase with triple polo box architecture, which serves as an indispensable regulator of centriole duplication (10)(11)(12). In recent years, several studies have demonstrated that PLK4 promotes tumorigenesis in solid tumors, such as colorectal, prostate and non-small cell lung cancer (13)(14)(15). For example, a previous study indicated that PLK4 facilitated cell viability and proliferation in colorectal cancer cells by inhibiting the Wnt/β-catenin signaling pathway (13).…”

Effects of the PLK4 inhibitor Centrinone on the biological behaviors of acute myeloid leukemia cell lines

“…Previous studies indicated that PLK4 was high expressed in several human cancers, including hepatocellular carcinoma, colorectal cancer, gastric cancer, glioblastoma, neuroblastoma, breast cancer, and lung cancer ( Zhang et al, 2021 ), and had a close relationship with the progression of cancers. Due to the vital roles of PLK4 in the regulation of centrosome replication and the pathology of cancers, more and more PLK4 inhibitors were developed, such as Centrinone, Centrinone-B, CFI-400495 and YLT-11 ( Mason et al, 2014 ; Wong et al, 2015 ; Kawakami et al, 2018b ; Denu et al, 2018 ; Lei et al, 2018 ; Kerschner-Morales et al, 2020 ; Zhao et al, 2021 ; Singh et al, 2022 ). The already known studies information about above PLK4 inhibitors, such as structures, mainly studied cancer cells and effects of these inhibitors on the biological behaviors have been summarized in Table 1 .…”