Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

Abstract

Polo-like kinases (PLKs) belong to a five-membered family of highly conserved serine/threonine kinases (PLK1-5) that play differentiated and essential roles as key mitotic kinases and cell cycle regulators and with this in proliferation and cellular growth. Besides, evidence is accumulating for complex and vital non-mitotic functions of PLKs. Dysregulation of PLKs is widely associated with tumorigenesis and by this, PLKs have gained increasing significance as attractive targets in cancer with diagnostic, prognostic and therapeutic potential. PLK1 has proved to have strong clinical relevance as it was found to be over-expressed in different cancer types and linked to poor patient prognosis. Targeting the diverse functions of PLKs (tumor suppressor, oncogenic) are currently at the center of numerous investigations in particular with the inhibition of PLK1 and PLK4, respectively in multiple cancer trials. Functions of PLKs and the effects of their inhibition have been extensively studied in cancer cell culture models but information is rare on how these drugs affect benign tissues and organs. As a step further towards clinical application as cancer targets, mouse models therefore play a central role. Modelling PLK function in animal models, e.g., by gene disruption or by treatment with small molecule PLK inhibitors offers promising possibilities to unveil the biological significance of PLKs in cancer maintenance and progression and give important information on PLKs’ applicability as cancer targets. In this review we aim at summarizing the approaches of modelling PLK function in mice so far with a special glimpse on the significance of PLKs in ovarian cancer and of orthotopic cancer models used in this fatal malignancy.

Polo-Like Kinase 2 Plays an Essential Role in Cytoprotection against MG132-Induced Proteasome Inhibition via Phosphorylation of Serine 19 in HSPB5

“…We focused on PLK2 among the candidate proteins predicted to bind HSPB5 by MG132 treatment. PLK2 belongs to the “Polo” family of serine/threonine kinases and functions in mitosis and cell cycle regulation [ 24 ]. PLK2 showed a significant value of emPAI, as acquired by mass spectrometry, and emPAI increased with ER stress ( Table 1 ).…”

“…In this study, we explored the binding proteins of HSPB5 and newly identified PLK2, which binds to HSPB5 under ER stress by MG132 treatment. PLK2 belongs to the polo-like kinase family and has recently been investigated as a therapeutic target for tumors [ 24 ]. We further showed that PLK2 phosphorylates serine 19, one of the three phosphorylation sites of HSPB5 [ 35 , 40 ], suppresses apoptosis induced by MG132-induced ER stress.…”

Clinicopathological Significance of AKT1 and PLK1 Expression in Oral Squamous Cell Carcinoma

“…In contrast, PLK1 inhibitors act on multiple stages of cell mitosis, such as Annotation: R > 0:8: highly correlated; 0:5 < R < 0:8: moderate correlation; 0:3 < R < 0:5: low correlation; R < 0:3: irrelevant. 7 Disease Markers blocking centrosome maturation, spindle formation, and cytokinesis, thereby disrupting cell division and cycle progression and ultimately leading to tumor cell death [12]. Studies have shown that PLK1 is overexpressed in colorectal cancer [36], pancreatic cancer [37], gastric cancer [38], prostate cancer [39], thyroid cancer [40], bladder cancer, and other tumors [41], and the high expression of PLK1 indicates poor clinical prognosis.…”

“…Polo-like kinase 1 (PLK1), a member of the PLK family, is a serine/threonine protein kinase and is widely recognized as an oncogene. PLK1 plays a crucial role in the cell cycle and drives cell proliferation by promoting mitosis and cytokinesis [11][12][13]. In addition, PLK1 also has roles in meiosis, including regulating cancer cell invasiveness and preventing cancer cell apoptosis [14].…”

Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth

“…PLK1 (Polo-like kinase 1) is a member of the polo-like kinase family of serine/threonine protein kinases and plays an important role in regulating the cell cycle. PLK1 contains an N-terminal catalytic domain, C-terminal polo-box domain (PBD), and a phosphopeptide connecting region in the middle that connects both N- and C-terminal domains of the PLK1 [ 5 ]. The C-terminal PBD consists of two polo-box structures, an important feature of PLK family proteins, whereas the N-terminal catalytic domain of PLK1 is a Serine/Threonine kinase domain [ 6 ].…”