Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role

Abstract

The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear. Deregulation of the pathway may be caused by overexpression or downregulation of a wide range of antagonist proteins. Although there is growing information related to function and regulation of Dickkopf (DKK) proteins, their pharmacological potential as cancer therapeutics still has not been fully developed. This review provides an update on the role of DKK proteins in cancer and possible potential as therapeutic targets for the treatment of cancer; available compounds in pre-clinical or clinical trials are also reviewed.

Keywords: DKK; Dickkopf; Wnt antagonists; Wnt signaling.

Figure 1

Domain structure of human DKK protein family. Cysteine-rich domain 1 (Cys1) and Cys2 domains are shared by the four members of DKK family. Signal peptide, coiled-coil region and glycosylation sites are also shown.

Figure 2

Strategies to target DKK proteins. (A) When Wnt signaling is active, Wnt ligands bind to Fz receptor and the LRP5/6 co-receptor, thereby producing the inhibition of the degradation complex (APC-Axin-CK1α-GKS3β) and consequent β-catenin accumulation and stabilization. (B) If Wnt ligands do not bind, the destruction complex is active and the degradation of β-catenin is produced. (C) DKK-1 blocks Wnt and LPR5/6 interaction by activating the degradation complex and further inhibition of the signaling by β-catenin degradation. NCI8642, RH2-18, BHQ880 and DKN-01 are able to block this specific DKK-1 activity. (D) The interaction of DKK-1 with LPR5/6 and Kremen proteins produces DKK-1 internalization together with the LPR5/6 receptor. The WAY-262611 compound can inhibit Kremen-LRP5/6-Dkk-1 complex formation. (E) Activators of DKK-1 such as vitamin D analogs induce the transcription of DKK-1 gene thereby increasing DKK-1 protein levels and the subsequent Wnt signaling inhibition.