PLK1 Polo-Box: An Emerging Target in Cancer Therapy

Authors: Esra Tiras (1), Anshu Cherukumilli (2), Begum Hussain (3), Julie Fang (4), and Rohan Shah (5)

Editor: Monsurat Lawal, Ph.D.

Author Affiliations: (1) University of Virginia, (2) Montgomery High School, (3) Pinnacle Academy, (4) Johns Hopkins University, (5) Poolesville High School

Introduction

Cancer, a term that sparks confusion, worry, and an overwhelming sense of fear, is known for its incredibly high mortality rate (an average of 18%) and the seemingly impossible ordeal of finding its cure [1]. This article explores the potential of targeting polo-like kinase 1 (PLK1) for cancer therapy, emphasizing the polo-box domain (PBD), and highlights the complexities of cancer, with a focus on breast cancer.

Understanding Cancer and Cell Cycle Regulation

Cancer occurs when mechanisms to regulate cell growth are disabled or malfunction. Imagine a cell's life as a journey through phases called the cell cycle (Figure 1). Interphase, the longest phase, is where the cell grows and prepares for division. Before entering the division phase (M phase), the cell undergoes rigorous checks at specific checkpoints (G1, S, G2) to ensure its DNA is undamaged and ready for replication [2]. This screening ensures that only healthy cells divide and prevents errors from being passed on. If a cell is damaged, tumor suppressor genes are expressed, causing the cell to exit the cell cycle and enter a phase of either cell repair or apoptosis, the self-destruction of the cell.

In healthy cells, progression through checkpoints is aided by proto-oncogenes, which enable cyclin-dependent kinases (CDKs) protein expression. CDKs bind to cyclins, releasing transcription factor proteins such as E2F to allow the cell to move from checkpoint to checkpoint. These CDKs also help to continue a phosphorylation chain in which other kinases, including polo-like kinases (PLKs), are activated [3]. Tumor suppressor genes act as a "brake" to prevent damaged cells from advancing and replicating through the cell cycle, while proto-oncogenes act as a "gas pedal" to allow healthy cells to move through the cycle, allowing the entire cell to sustain itself [4]. Mutations in either mechanism can lead to cancer.

Breast Cancer: A Prevalent Challenge

Breast cancer is one of the most prevalent cancers, affecting millions of women worldwide [5]. While most breast lumps are benign and do not spread or become life-threatening, they can increase a woman's risk of developing breast cancer. Most breast cancers are carcinomas that start in the epithelial cells covering most of the body's tissues. When carcinomas form in the breast, they are called adenocarcinomas, which originate in the lobules (glands that make milk) or ducts (transport milk from lobules to nipples). The two most common breast cancers are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), as depicted in Figure 2. IDC starts in the cells in the milk duct in the breast, later growing into nearby breast tissue and potentially metastasizing to other body tissues. ILC starts in the lobules and can spread to other tissues in the breast and body [6].

The Role of PLK1 in Cancer

PLKs are serine/threonine kinases, first identified in Drosophila as a Polo mutant over 27 years ago [7]. In mammalian cells, four PLK family members (PLK1 to PLK4) are expressed, and recently, PLK5 has been characterized in mouse and human cells [8]. PLK1 is a key regulator for several cellular events, such as DNA activation, mitotic entry, and cytokinesis (Figure 3). Overexpression of PLK1 has been observed in several types of cancer, including stage IV or metastatic breast cancer [9].

The PBD of PLK1 is critical for its localization to specific subcellular structures and interaction with phosphorylated substrates. Targeting and inhibiting the PBD of PLK1 could reduce cancer cell proliferation and slow down tumor growth [10]. PBD inhibition can lead to mitotic catastrophe, a form of cell death due to premature or inappropriate entry of cells into mitosis, effective against rapidly dividing cells.

Targeting the Polo-Box Domain: A Promising Approach

Inhibiting the PBD of PLK1 offers a unique and potentially more specific approach to cancer treatment. Researchers have invested in designing and identifying potential inhibitors specific to the PBD, including small molecule inhibitors and peptide-like molecules that mimic the phosphorylated substrates of PLK1. Although there is no approved PLK1 PBD inhibitor yet, the specificity of these inhibitors could lead to groundbreaking outcomes. PBD-targeted drugs could be more specific, reducing side effects on healthy cells.

Conclusion

PLK1 inhibition via the polo-box domain offers a unique and potentially more specific approach to cancer treatment. However, developing drugs with high specificity and affinity for individual binding motifs remains challenging. Understanding the full consequences of disrupting specific PBD interactions within the complex cellular network requires further research. Significant research and development are needed to overcome current challenges and translate this exciting concept into effective clinical therapies.

Glossary

1. Cell Cycle: The series of phases that a cell goes through as it grows and divides. It includes interphase (growth and DNA replication) and mitosis (cell division).

2. Checkpoint: Specific points in the cell cycle where the cell assesses whether to proceed with division, ensuring DNA is undamaged and correctly replicated.

3. Tumor Suppressor Genes: Genes that help prevent uncontrolled cell growth by halting the cell cycle or initiating apoptosis (cell death) in damaged cells.

4. Proto-Oncogenes: Genes that promote cell division and survival, which can lead to cancer if mutated or overexpressed.

5. Cyclin-Dependent Kinases (CDKs): Enzymes that, when bound to cyclins, regulate progression through the cell cycle by phosphorylating target proteins.

6. Phosphorylation: The addition of a phosphate group to a molecule, often used to activate or deactivate proteins and enzymes.

7. Polo-Like Kinases (PLKs): A family of serine/threonine kinases involved in various stages of cell division and mitosis.

8. Polo-Box Domain (PBD): A domain within PLK1 that is essential for its localization and interaction with phosphorylated substrates.

9. Mitotic Catastrophe: A form of cell death that occurs due to errors in mitosis, often resulting from premature or inappropriate entry into mitosis.

10. Metastasis: The spread of cancer cells from the original tumor site to other parts of the body, forming new tumors.

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