CKAP4 is identified as a receptor for Dickkopf in cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Dickkopf-1 (DKK-1) is a secretory protein known as a Wnt antagonist.
• While DKK-1 can suppress tumorigenesis in some contexts, it is frequently upregulated in various cancers, correlating with poor prognosis.
• The Wnt-independent mechanisms driving DKK-1's role in cancer cell proliferation remain largely unelucidated.

Purpose of the Study:

• To investigate novel Wnt-independent pathways through which Dickkopf-1 (DKK-1) promotes cancer cell proliferation.
• To identify potential therapeutic targets for DKK-1-driven cancers.

Main Methods:

• The study examined the interaction between Dickkopf-1 (DKK-1) and cytoskeleton-associated protein 4 (CKAP4).
• AKT activation downstream of this interaction was assessed.
• Expression levels of DKK-1 and CKAP4 were analyzed in pancreatic and lung cancer samples.
• Efficacy of targeting the DKK-1-CKAP4 interaction using an anti-CKAP4 antibody was evaluated in murine xenograft models.

Main Results:

• Dickkopf-1 (DKK-1) was found to interact with cytoskeleton-associated protein 4 (CKAP4), leading to AKT activation.
• Both DKK-1 and CKAP4 were frequently overexpressed in pancreatic and lung cancers.
• Administration of an anti-CKAP4 antibody effectively inhibited tumor formation in preclinical cancer models.

Conclusions:

• A novel DKK-1-mediated pathway involving CKAP4 and AKT activation in a Wnt-independent manner was identified.
• This pathway contributes to cancer cell proliferation and tumor formation.
• Cytoskeleton-associated protein 4 (CKAP4) represents a promising therapeutic target for specific DKK-1-associated cancers.