The Emerging Role of Polo-Like Kinase 1 in Epithelial-Mesenchymal Transition and Tumor Metastasis

Abstract

Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays a key role in the regulation of the cell cycle. PLK1 is overexpressed in a variety of human tumors, and its expression level often correlates with increased cellular proliferation and poor prognosis in cancer patients. It has been suggested that PLK1 controls cancer development through multiple mechanisms that include canonical regulation of mitosis and cytokinesis, modulation of DNA replication, and cell survival. However, emerging evidence suggests novel and previously unanticipated roles for PLK1 during tumor development. In this review, we will summarize the recent advancements in our understanding of the oncogenic functions of PLK1, with a focus on its role in epithelial-mesenchymal transition and tumor invasion. We will further discuss the therapeutic potential of these functions.

Keywords: EMT; PLK1; cancer therapy; drug resistance; tumor invasion and metastasis.

Figure 1

A schematic diagram illustrating the domain structures of the human polo-like kinase (PLK) family of proteins (PLK1-5). The number of amino acids in each family member is indicated on the right. The location of the kinase domains is shown in orange, whereas the polo-box domains (PBD), made of two polo-boxes (PB), are represented in blue. These two domains are separated by the interdomain linker, which comprises a destruction box (D-Box) indicated in green. The numbers indicate the first and the last residues of these domains in human PLKs. Residues that are essential for ATP-binding and enzymatic activation (T-loop) within the kinase domains, and for phosphoselectivity within the polo-box domains, are depicted. Sequence identities with the corresponding domains in PLK1 are provided in percentages. Two distinct strategies for targeting PLK1 are included: ATP-competitive inhibitors targeting the catalytic activity of PLK1, and PBD-binding antagonists competitively inhibiting the function of PBD.

Figure 2

Role of polo-like kinase 1 (PLK1) overexpression in cancer. In addition to its role in promoting cancer cell proliferation and suppressing apoptosis, PLK1 overexpression has also been reported to have important roles in oncogenic transformation, tumor initiation and survival, epithelial-mesenchymal transition (EMT) induction, tumor migration and invasion, and therapeutic resistance.

Figure 3

An overview of signaling cascades involved in PLK1-induced EMT. PLK1 activates the MAPK pathway by directly binding and phosphorylating CRAF. The activated MAPK pathway causes transcriptional upregulation of Fra1, which in turn triggers the accumulation of ZEB1/2, thus orchestrating the transcriptional network necessary for the EMT program. PLK1 also induces EMT through AKT or FoxM1-dependent pathways. Together, these signaling events contribute to EMT induction and associated events (such as invasion and therapeutic resistance) in tumor cells overexpressing PLK1.