The Emerging Role of CKAP4 in GI Cancer: From Molecular Pathways to Clinical Applications

Abstract

Cytoskeleton-associated protein 4 (CKAP4) has emerged as a critical player in gastrointestinal (GI) cancer progression, diagnosis, and therapy. This comprehensive review synthesizes current knowledge on CKAP4's multifaceted roles across GI malignancies, providing novel insights into its mechanisms of action and clinical potential. Its interaction with DKK1 and subsequent activation of the PI3K/AKT pathway underscores its role in promoting tumor growth. This review also highlights novel insights into CKAP4's mechanisms of action beyond the well-established DKK1-CKAP4 axis, including its interaction with integrin β1 and involvement in angiogenesis through the FMNL2/EGFL6/CKAP4/ERK pathway. CKAP4's impact on tumor microenvironment and immune evasion is elucidated, offering a new perspective on its contribution to cancer progression. In addition, CKAP4 arises as a promising serum biomarker for early detection and prognosis across multiple GI cancers, emphasizing its potential superiority over traditional markers. The therapeutic potential of targeting CKAP4 is extensively explored, including novel approaches like anti-CKAP4 antibodies and aptamers, and their synergistic effects with existing treatments. By integrating findings from esophageal, gastric, pancreatic, and colorectal cancers, this review provides a unique, comprehensive overview of CKAP4 in GI oncology, underscoring CKAP4's potential to revolutionize GI cancer diagnosis and treatment and paving the way for future translational research.

Keywords: CKAP4; biomarker; gastrointestinal malignancies; molecular therapy.

Figure 1

CKAP4 location: (A) CKAP4 binds to microtubules stabilizing ER. CKAP4′s phosphorylation is crucial for its role. (B) CKAP4′s palmitoylation leads to its transportation to PM acting as receptor for various ligands. (C) CKAP4 located in PM is secreted via exosomes, resulting in its detection in serum. CKAP4, Cytoskeleton-associated protein 4; ER, endoplasmic reticulum; PM, plasma membrane; DKK1, Dickkopf 1; APF, antiproliferative factor; t-PA, tissue plasminogen activator; SP-A, surfactant protein A. Created in BioRender 201. Despotidis, M. (2025) https://BioRender.com/mhuvdvf (accessed on 2 September 2025).

Figure 2

(A) DKK1–CKAP4 axis, (B) possible ways of inhibition of CKAP4 signaling in GI malignancies. CKAP4, cytoskeleton-associated protein 4; DKK, Dickkopf; EGFL6, epidermal growth factor-like protein 6; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; AKT, protein kinase B; FOXM1, forkhead box M1; siRNAs, small interfering RNAs. Created in BioRender 201. Despotidis, M. (2025) https://BioRender.com/e5q6awl (accessed on 2 September 2025).