Polo-like Kinase 3 Functions as a Tumor Suppressor and Is a Negative Regulator of Hypoxia-Inducible Factor-1α under Hypoxic Conditions

Abstract

Polo-like kinase 3 (Plk3) is an important mediator of the cellular responses to genotoxic stresses. In this study, we examined the physiologic function of Plk3 by generating Plk3-deficient mice. Plk3 À/À mice displayed an increase in weight and developed tumors in various organs at advanced age. Many tumors in Plk3 À/À mice were large in size, exhibiting enhanced angiogenesis. Plk3 À/À mouse embryonic fibroblasts were hypersensitive to the induction of hypoxiainducible factor-1A (HIF-1A) under hypoxic conditions or by nickel and cobalt ion treatments. Ectopic expression of the Plk3-kinase domain (Plk3-KD), but not its Polo-box domain or a Plk3-KD mutant, suppressed the nuclear accumulation of HIF-1A induced by nickel or cobalt ions. Moreover, hypoxiainduced HIF-1A expression was tightly associated with a significant down-regulation of Plk3 expression in HeLa cells. Given the importance of HIF-1A in mediating the activation of the ''survival machinery'' in cancer cells, these studies strongly suggest that enhanced tumorigenesis in Plk3-null mice is at least partially mediated by a deregulated HIF-1 pathway.

BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity

“…Nevertheless, Plk3 is apparently not essential for cell cycle progression, as Plk3-/-mice do not show growth defects (45). Interestingly, Plk1 and Plk3 have recently been proposed as tumor suppressor genes based on the fact that Plk1+/-and Plk3-/-mice seem to develop tumors with somewhat increased frequency (45,46).…”

Phase I Study of GSK461364, a Specific and Competitive Polo-like Kinase 1 Inhibitor, in Patients with Advanced Solid Malignancies

“…When considering on target effects, a recent meta-analysis of antiangiogenic drug trials showed an 11.9% incidence of VTE in patients with cancer receiving the anti-VEGF antibody bevacizumab (24). Enhanced angiogenesis was observed in PLK3 À/À mice and Plk3 is thought to be a negative regulator of HIF1a and thus VEGF (25). An hypothesis is that members of the Plk family exert competing control over vascular signaling and that targeted depletion of Plk1 disrupts this balance in favor of the antiangiogenic influence of Plk3 (25).…”

“…Enhanced angiogenesis was observed in PLK3 À/À mice and Plk3 is thought to be a negative regulator of HIF1a and thus VEGF (25). An hypothesis is that members of the Plk family exert competing control over vascular signaling and that targeted depletion of Plk1 disrupts this balance in favor of the antiangiogenic influence of Plk3 (25). However, there is no preclinical data to support this hypothesis and VTE events have not been observed as a class effect.…”

Aurora-A and hBora Join the Game of Polo

“…Moreover, caution should be taken when using Plk inhibitors as antitumor drugs, as all currently available compounds can also inhibit Plk3 activity at least in vitro. There is accumulating evidence that, in fact, Plk3 may act as a tumor suppressor, and that its undesired inhibition may thus induce secondary tumors (24). Solving the crystal structure of the Plk1 kinase domain and identification of critical specificitydetermining residues will hopefully enable the development of a selective Plk1 inhibitor (25,26).…”