Abstract
The polo family serine threonine kinase Plk4 has been proposed as a therapeutic target in advanced cancers based on increased expression in primary human cancers, facilitation of tumor growth in murine xenograft models, and centrosomal amplification induced by its overexpression. However, both the causal link between these phenomena and the feasibility of selective Plk4 inhibition remain unclear. Here we characterize Plk4-dependent cancer cell migration and invasion as well as local invasion and metastasis of cancer xenografts. Plk4 depletion suppressed cancer invasion and induced an epithelial phenotype in poorly differentiated breast cancer cells. In an unbiased BioID screen for Plk4 interactors, we identified members of the Arp2/3 complex and confirmed a physical and functional interaction between Plk4 and Arp2 in mediating Plk4-driven cancer cell movement. This interaction is mediated through the Plk4 Polo-box 1-Polo-box 2 domain and results in phosphorylation of Arp2 at the T237/T238 activation site, which is required for Plk4-driven cell movement. Our results validate Plk4 as a therapeutic target in cancer patients and reveal a new role for Plk4 in regulating Arp2/3-mediated actin cytoskeletal rearrangement. Cancer Res; 77(2); 434-47. ©2016 AACR.
Highlights
Polo like kinase 4 (Plk4) is a serine threonine kinase that localizes to the centriole throughout the cell cycle, and is essential for centriole duplication [1,2,3,4]
We found that Arp2 phosphorylation at T237/T238 was significantly greater in HeLa cells transfected with wild-type Plk4, than cells transfected with kinase-dead Plk4 (Fig. 6E, top; Supplementary Fig. S9A), and was reduced in Plk4-depleted versus control cells (Fig. 6E, bottom), in keeping with the possible phosphorylation of Arp2 by Plk4 at this site in cellulo
The enhanced wound healing seen in U2OS cells stably expressing Plk4 was diminished by the Arp2 inhibitor CK-666 (Fig. 7D). These results indicate that Arp2 binds to Plk4, is phosphorylated and activated in its presence, and this is required for stimulation of cancer cell motility by Plk4
Summary
Polo like kinase 4 (Plk4) is a serine threonine kinase that localizes to the centriole throughout the cell cycle, and is essential for centriole duplication [1,2,3,4]. Increased expression of Plk is described in a variety of common human epithelial malignancies, and is associated with inferior survival in several large cohorts of breast cancer patients [5,6,7]. High levels of Plk mRNA are found in the triple-negative human breast cancers that are resistant to conventional systemic therapy, stimulating interest in Plk as a therapeutic target [8]. Upregulation of Plk expression independently induces aneuploidy, loss of cell polarity, and hyperplasia in some nontransformed cell lines and proliferative tissues [9, 10]. In the context of p53 dysfunction, increased Plk expression contributes to aneuploidy and tumorigenesis [10, 11]. Plk works as a haploinsufficient tumor suppressor in some contexts: Plk4þ/À mice are predisposed to form multipolar
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