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.

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

“…DKK1/2 antagonizes the Wnt/β-catenin pathway through extracellular interactions with the Wnt co-receptors LRP5 / 6 , which prevents the formation of FZD:LRP complexes ( Figure 1 ). DKK1/2 Wnt/β-catenin signaling suppression is potentiated by interaction with the co-receptor KREMEN (KREMEN1/2), whereas DKK4 interactions with LRP5 / 6 and KREMEN are less well characterized [ 147 ]. The role of DKK3 and Soggy in Wnt/β-catenin signaling is also unclear, as they are not known to interact with LRP5 / 6 or KREMEN [ 147 , 148 ].…”

“…DKK1/2 Wnt/β-catenin signaling suppression is potentiated by interaction with the co-receptor KREMEN (KREMEN1/2), whereas DKK4 interactions with LRP5 / 6 and KREMEN are less well characterized [ 147 ]. The role of DKK3 and Soggy in Wnt/β-catenin signaling is also unclear, as they are not known to interact with LRP5 / 6 or KREMEN [ 147 , 148 ]. DKKs can also regulate the Wnt/PCP pathway [ 149 , 150 ], adding to the complexity of Wnt signaling regulation [ 147 , 148 ].…”

“…The role of DKK3 and Soggy in Wnt/β-catenin signaling is also unclear, as they are not known to interact with LRP5 / 6 or KREMEN [ 147 , 148 ]. DKKs can also regulate the Wnt/PCP pathway [ 149 , 150 ], adding to the complexity of Wnt signaling regulation [ 147 , 148 ]. DKK-mediated cellular processes can also occur independently of the Wnt cascade.…”

“…Currently, DKKs are considered to play a dual role in cancer, possessing both oncogenic and tumor-suppressive functions depending on the context and tumor type (reviewed in [ 147 ]). In prostate cancer, DKK1–4 genetic mutations are rare in primary and metastatic prostate cancer patients (0–0.68% incidence, Tables S1–S4 ) [ 64 , 65 , 66 ].…”

“…DKK2 can both activate and inhibit Wnt/β-catenin signaling, depending on the cellular context, such as LRP5 / 6 abundance and DKK1 expression, as DKK1 can inhibit DKK2 [ 147 , 148 ]. In human prostate cancer cells, DKK2 depletion is reported to suppress cell proliferation and invasion, attributable to reduced β-catenin and Wnt transcriptional targets CyclinD1 and Myc [ 155 ].…”