PLK4, or Polo-like kinase 4, is an important protein within human cells, playing a fundamental role in cellular health. Its proper function is crucial for cell division, which ensures the growth, repair, and maintenance of tissues in the body. Understanding PLK4’s normal activities provides insight into how cells manage their internal processes.
The Cell’s Master Duplicator
PLK4 normally functions as a regulator of centriole duplication, an event occurring once per cell cycle. Centrioles are small, cylindrical structures that form the core of centrosomes, which act as the cell’s main organizing centers for microtubules. Microtubules, the cell’s internal scaffolding, are essential for forming spindle poles during cell division.
During the S phase of the cell cycle, PLK4 initiates the assembly of a new daughter centriole, called a procentriole, next to the existing mother centriole. PLK4 recruits proteins like STIL and Sas-6 to the site where the new centriole will form. The accurate duplication of centrosomes ensures that when a cell divides, each new daughter cell receives a complete and correct set of chromosomes.
When PLK4 Goes Wrong
When the activity of PLK4 is disrupted, whether overactive or underactive, it can lead to serious consequences for the cell. An imbalance in PLK4 levels can result in an abnormal number of centrosomes. For example, even a modest increase in PLK4 levels can cause centrosome amplification.
These errors in centrosome numbers then lead to problems during cell division in how chromosomes are separated. This can cause a condition known as aneuploidy, where cells have an abnormal number of chromosomes. Such chromosomal imbalances create genomic instability within the cell, making it prone to further errors and a breakdown in normal cellular functions.
PLK4’s Role in Cancer Development
The genomic instability resulting from dysregulated PLK4 activity contributes to the development and progression of cancer. When a cell accumulates an abnormal number of chromosomes, it becomes more susceptible to mutations and uncontrolled growth. This unstable genetic makeup allows cells to acquire characteristics typical of cancer, such as rapid proliferation.
PLK4 overexpression has been observed in many human cancers, including breast, colorectal, ovarian, lung, and gastric cancers, as well as melanoma and lymphoma. In some cases, increased PLK4 expression is associated with larger tumor sizes and the spread of cancer to lymph nodes. Research has shown that even transient increases in PLK4 expression can lead to centrosome amplification and aneuploidy, which can accelerate tumor formation, especially with genetic vulnerabilities like a compromised p53 tumor suppressor gene.
Targeting PLK4 for Therapy
Given its involvement in cancer, PLK4 has emerged as a promising target for new therapies. Inhibiting PLK4 in cancer cells exploits their existing genomic instability, pushing them beyond a tolerable threshold to induce cell death or stop their uncontrolled growth. PLK4 inhibitors are designed to bind to and block the enzyme’s activity, preventing its role in centriole duplication and spindle formation.
Several small molecule PLK4 inhibitors, such as CFI-400945 and centrinone, are being investigated. CFI-400945, an ATP-competitive inhibitor that has shown anti-tumor activity in preclinical models, including patient-derived tumor xenografts. This drug has progressed into Phase I clinical trials for patients with advanced solid tumors and certain genetic changes, including relapsed and refractory acute myeloid leukemia and myelodysplastic syndrome. Other PLK4 inhibitors, like RP-1664, are also in Phase 1 trials for specific solid tumors.