Related Experiment Video
Updated: Sep 29, 2025
Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells
Published on: August 21, 2013
PLK4 is upregulated in prostate cancer and its inhibition reduces centrosome amplification and causes senescence
Chandra K Singh1, Ryan A Denu2,3,4, Minakshi Nihal1
1Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
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.
Insights
Polo-like kinase 4 (PLK4) drives prostate cancer (PCa) growth by promoting centriole overduplication and centrosome amplification (CA). Inhibiting PLK4 halts PCa cell proliferation and induces senescence, suggesting it as a potential therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Prostate cancer (PCa) remains a leading cause of cancer morbidity and mortality in men.
- Identifying novel molecular targets is crucial for developing new, mechanistically driven PCa treatments.
- Polo-like kinase 4 (PLK4) regulates centriole duplication and centrosome amplification (CA), key cellular processes potentially involved in cancer development.
Purpose of the Study:
- To investigate the role of PLK4 in PCa.
- To determine the prevalence and causes of centrosome amplification (CA) in PCa.
- To evaluate the therapeutic potential of PLK4 inhibition in PCa.
Main Methods:
- Human PCa tissue microarrays were used to assess CA prevalence and correlate it with Gleason score.
- Centriole overduplication versus cell doubling as causes of CA were distinguished using centriole staining.
- PLK4 expression was analyzed in PCa tissues and cell lines, and the effects of PLK4 inhibitors (CFI-400945, centrinone-B) on PCa cells were determined.
Main Results:
- PCa tissues exhibited significantly higher CA than benign prostate tissues, with CA correlating positively with Gleason score.
- Centriole overduplication was identified as the primary cause of CA in PCa, rather than cell doubling events.
- PLK4 was overexpressed in PCa, and its inhibition by CFI-400945 and centrinone-B reduced PCa cell growth, viability, and colony formation, while inducing cell cycle arrest and senescence.
Conclusions:
- Centrosome amplification (CA) is common in PCa and mainly results from centriole overduplication.
- PLK4 is overexpressed in PCa and drives CA.
- Inhibition of PLK4 presents a promising therapeutic strategy for PCa by inducing cell cycle arrest and senescence.
Related Concept Videos
02:34Inhibition of Cdk Activity
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:23Abnormal Proliferation
01:22PI3K/mTOR/AKT Signaling Pathway
01:23Negative Regulator Molecules
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...