Polo-like kinase 1 induces epithelial-to-mesenchymal transition and promotes epithelial cell motility by activating CRAF/ERK signaling.

Jianguo Wu,Paul B Fisher,Andrei I Ivanov,Zheng Fu

doi:10.7554/elife.10734

Abstract

Polo-like kinase 1 (PLK1) is a key cell cycle regulator implicated in the development of various cancers, including prostate cancer. However, the functions of PLK1 beyond cell cycle regulation remain poorly characterized. Here, we report that PLK1 overexpression in prostate epithelial cells triggers oncogenic transformation. It also results in dramatic transcriptional reprogramming of the cells, leading to epithelial-to-mesenchymal transition (EMT) and stimulation of cell migration and invasion. Consistently, PLK1 downregulation in metastatic prostate cancer cells enhances epithelial characteristics and inhibits cell motility. The signaling mechanisms underlying the observed cellular effects of PLK1 involve direct PLK1-dependent phosphorylation of CRAF with subsequent stimulation of the MEK1/2-ERK1/2-Fra1-ZEB1/2 signaling pathway. Our findings highlight novel non-canonical functions of PLK1 as a key regulator of EMT and cell motility in normal prostate epithelium and prostate cancer. This study also uncovers a previously unanticipated role of PLK1 as a potent activator of MAPK signaling.

Highlights

Mammalian polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in the regulation of the cell cycle (Barr et al, 2004; Llamazares et al, 1991)
To examine the expression level and activity status of Polo-like kinase 1 (PLK1) in a panel of prostate cancer (PCa) cell lines, we performed immunobloting analysis using antibodies that recognize total PLK1 or its active form, phosphorylated at Tyrosine 210. Both the protein abundance and activity of PLK1 were elevated in PCa cell lines when compared to RWPE-1 cells, which is consistent with the PLK1 expression profile in PCa tissue specimens reported by another group (Weichert et al, 2004)
The present study revealed unanticipated non-canonical functions of PLK1 as a potent inducer of epithelial-to-mesenchymal transition (EMT) and a stimulator of the motile phenotype of prostate epithelial cells

Summary

Introduction

Mammalian polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in the regulation of the cell cycle (Barr et al, 2004; Llamazares et al, 1991). It contains a conserved N-terminal kinase catalytic domain and a C-terminal polo-box domain (PBD) that is involved in substrate binding. PLK1 is overexpressed in a variety of human tumors and its expression level often correlates with increased cellular proliferation, enhanced metastatic potential, and poor prognosis in cancer patients (Cholewa et al, 2013; Takai et al, 2005). Depleting PLK1 in U2OS cells abrogates anchorage-independent

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