Plk1 Inhibition Enhances the Efficacy of Androgen Signaling Blockade in Castration-Resistant Prostate Cancer

Abstract

Prostate cancer (PCa) is thought to be driven by oxidative stress, lipid metabolism, androgen receptor (AR) signaling and activation of the PI3K/AKT/mTOR pathway, but it is uncertain how they may become coordinated during progression to castration-resistant disease which remains incurable. The mitotic kinase polo-like kinase 1 (Plk1) is elevated in PCa where its expression is linked to tumor grade. Notably, Plk1 signaling and lipid metabolism were identified recently as two of the top five most upregulated pathways in a mouse xenograft model of human PCa. Herein, we show that oxidative stress activates both the PI3K/AKT/mTOR pathway and AR signaling in a Plk1-dependent manner in prostate cells. Inhibition of the PI3K/AKT/mTOR pathway prevented oxidative stress-induced activation of AR signaling. Plk1 modulation also affected cholesterol ester accumulation in PCa via the SREBP pathway. Lastly, Plk1 inhibition enhanced cellular responses to androgen signaling inhibitors (ASI) and overcame ASI resistance in both cultured PCa cells and patient-derived tumor xenografts. Given that activation of AR signaling and the PI3K/AKT/mTOR pathway is sufficient to elevate SREBP-dependent expression of key lipid biosynthesis enzymes in castration-resistant PCa, our findings argued that Plk1 activation was responsible for coordinating and driving these processes to promote and sustain the development of this advanced stage of disease. Overall, our results offer a strong mechanistic rationale to evaluate Plk1 inhibitors in combination drug trials to enhance the efficacy of androgen signaling inhibitors in castration-resistant prostate cancer.

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

“…Fifth, castration-induced elevations of Plk1 levels contribute to the constitutive activation of AR signaling, another major force in CRPC disease. Consequently, Plk1 inhibition enhances the efficacy of androgen signaling blockades in CRPC (15). The data presented here are surprising as they clearly show that one major side effect of inhibiting Plk1 is activation of the Wnt/␤-catenin pathway.…”

“…Several potent and selective ATP-competitive inhibitors of Plk1 have been shown to effectively inhibit tumor growth in in vivo studies (13,14). Additionally, we recently reported that inhibition of Plk1 enhances the efficacy of ASIs in CRPC (15). In this study, we discovered that depletion or inhibition of Plk1 significantly reduces phosphorylated ␤-catenin levels and thus the stabilization of ␤-catenin protein in various prostate cancer cell lines.…”

“…First, castration, the major approach to treat late-stage PCa, activates many downstream signaling pathways, in which Plk1 is one of the top five upregulated pathways in human PCa xenograft models (12). Second, among multiple castration-associated side effects, increased oxidative stress contributes to the elevation of Plk1 levels in an NF-B-dependent manner (15). Third, Plk1 phosphorylation of Clip-170 (37) and p150…”

“…Immunofluorescence (IF) staining was performed as described previously (15). Antibodies against ␤-catenin (catalog no.…”

MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing's sarcoma cells

“…Akt activates the mTOR signaling pathway (37) and represses p21, as well as Bax, to enhance cell proliferation preventing apoptosis (38,39). Therefore, Akt downregulation by PTEN in ES cells induced the upregulation of p21 and Bax, which might have resulted in cell cycle inhibition and apoptosis in ES cells.…”