Plk1 Phosphorylation of PTEN Causes a Tumor-Promoting Metabolic State

Abstract

f One outcome of activation of the phosphatidylinositol 3-kinase (PI3K) pathway is increased aerobic glycolysis, but the upstream signaling events that regulate the PI3K pathway, and thus the Warburg effect, are elusive. Increasing evidence suggests that Plk1, a cell cycle regulator, is also involved in cellular events in addition to mitosis. To test whether Plk1 contributes to activation of the PI3K pathway, and thus aerobic glycolysis, we examined potential targets of Plk1 and identified PTEN as a Plk1 substrate. We hypothesize that Plk1 phosphorylation of PTEN leads to its inactivation, activation of the PI3K pathway, and the Warburg effect. Our data show that overexpression of Plk1 leads to activation of the PI3K pathway and enhanced aerobic glycolysis. In contrast, inhibition of Plk1 causes markedly reduced glucose metabolism in mice. Mechanistically, we show that Plk1 phosphorylation of PTEN and Nedd4-1, an E3 ubiquitin ligase of PTEN, results in PTEN inactivation. Finally, we show that Plk1 phosphorylation of PTEN promotes tumorigenesis in both its phosphatase-dependent and -independent pathways, revealing potentially new drug targets to arrest tumor cell growth.

Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

“…We have also shown that Plk1 phosphorylation of Hbo1 and Orc2, two members of the DNA replication machinery, regulates DNA synthesis by affecting chromatin loading of prereplicative complexes (16,44). More recently, we discovered that Plk1 phosphorylation of PTEN leads to a tumor-promoting metabolic state with increased glycolysis and glutamine anaplerosis, two hallmarks of cancer cells (40). Of interest, others reported previously that Plk1 interacts with and phosphorylates axin and that Plk1 phosphorylation of axin is involved in proper centrosome formation.…”

“…Fourth, Plk1 phosphorylation of the PTEN tumor suppressor causes its inactivation and, thus, activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway, a major driving force for PCa progression (40). Fifth, castration-induced elevations of Plk1 levels contribute to the constitutive activation of AR signaling, another major force in CRPC disease.…”

Low-dose arsenic-mediated metabolic shift is associated with activation of Polo-like kinase 1 (Plk1)

“…12 For example, it was recently reported that Plk1 phosphorylation of PTEN leads to its inactivation, activation of PI3K/AKT/ mTOR pathway, metabolic switch from mitochondrial respiration to glycolysis. 13 Herein, we report that Plk1 is a critical downstream target of activated NF-kB caused by low-dose arsenic and that Plk1-dependent activation of the PI3K/AKT/ mTOR pathway contributes to the metabolic switch from oxidative phosphorylation to aerobic glycolysis.…”

“…Considering that Plk1 phosphorylation of HSP70 contributes to attenuation of high-dose arsenic trioxide (5 mM for 24 hours)-induced mitotic abnormalities, such as formation of elongated spindles, 5,10 and that Plk1 elevation leads to aerobic glycolysis, 13 we then asked whether low-dose arsenic affects the level of Plk1. Toward that end, proteins were prepared from liver, kidney, lung and bladder tissues of mice as described above.…”

“…13 Given that the PI3K/AKT/mTOR pathway is a central regulator of energy metabolism, we asked whether the PI3K/AKT/mTOR pathway is involved in low-dose arsenic-associated metabolic shift. Indeed, the PI3K/AKT/ mTOR pathway was activated by low-dose arsenic treatment, indicated by increased phosphorylation levels of AKT and S6 proteins (Fig.…”