Modulating polo-like kinase 1 as a means for cancer chemoprevention

Abstract

Naturally occurring agents have always been appreciated for their medicinal value for both their chemopreventive and therapeutic effects against cancer. In fact, the majority of the drugs we use today, including the anti-cancer agents, were originally derived from natural compounds, either in their native form or modified to enhance their bioavailability or specificity. It is believed that for maximum effectiveness, it will useful to design novel target-based agents for chemoprevention as well as the treatment of cancer. Recent studies have shown that the serine/threonine kinase polo-like kinase (Plk) 1 is widely overexpressed in a variety of cancers and is being increasingly appreciated as a target for cancer management. Additionally, several chemopreventive agents have been shown to inhibit Plk1 in cancer cells. In this review, we will discuss if Plk1 could also be a target for designing novel strategies for cancer chemoprevention.

Fig. 1

Structure and function of Plk1. A Plk1 structure. Polo-like kinase 1 (Plk1) consists of a highly conserved kinase activity domain and two polo box domains involved in self regulation, target binding, and localization. The ATP binding site is located at lysine-83, and a phospho-activation site is located at threonine-210. Plk1 activity is increased upon phosphorylation at threonine-210 by Aurora A in conjunction with Bora. B Plk1 functions. Plk1 mRNA, protein and activity levels begin to rise in S-phase, peaking at the G₂/M transition. These levels are relatively steady throughout mitosis but decline upon mitotic exit into G₁. During cell cycle progression, Plk1 regulates multiple targets, both directly and indirectly, involved in the G₂/M transition, spindle pole maturation (SPM), the spindle assembly checkpoint (SAC), and cytokinesis. (Cell cycle stages are not to scale.)

Fig. 2

Plk1 kinase activity inhibitors. These compounds have been shown to directly inhibit Plk1 kinase activity. However, many have off-target effects on multiple, closely related targets.

Fig. 3

Polo box domain inhibitors. These compounds have been shown to bind to the Polo box domains of Plk1. This binding alters Plk1 localization and binding to Plk1 targets.

Fig. 4

Compounds shown to decrease Plk1 mRNA or protein levels. Treatment of cells with these compounds has been shown to decrease Plk1 mRNA and/or protein levels. The cause of this decrease in some instances is due to a G₁ or S arrest, which would naturally decrease Plk1 levels due to Plk1 transcription and translation occurring mainly leading up to and during mitosis.