CPZ promotes the proliferation of gastric cancer by activating the Wnt pathway through binding with DVL2

Gastric cancer (GC) is one of the most prevalent and heterogeneous malignancies worldwide, with treatment outcomes often hindered by delayed diagnosis and limited therapeutic options. Consequently, identifying novel targets for GC diagnosis and treatment is of significant clinical relevance. This study investigated the role of CPZ in GC progression and explored its molecular mechanisms and potential as a prognostic marker and therapeutic target.

Bioinformatics analysis and clinical pathological evaluations were conducted to assess CPZ expression in GC and its correlation with clinical parameters. In vivo and in vitro experiments, including CCK8 proliferation assays, flow cytometry, and xenograft mouse models, were employed to confirm the impact of CPZ on GC malignancy. Potential molecular mechanisms through which CPZ regulates GC cell biological functions were identified and validated using immunoprecipitation mass spectrometry (IP-MS), co-immunoprecipitation (Co-IP), protein truncation assays, GST-pull down assays, and Western blotting. The CPZ inhibitor PF-573228 was identified through screening a small-molecule compound library.

CPZ expression was significantly upregulated in GC (tumor tissues vs. normal tissues = 54.3% vs. 10.1%), correlating with unfavorable clinical pathological parameters and poor prognosis. CPZ directly interacts with DVL2 via its C-terminal domain (187-581aa). Its role in promoting tumorigenesis (both in vivo and in vitro) by fostering GC proliferation and regulation of cell cycle distribution is partially dependent on CPZ-DVL2 interaction, which activates the Wnt/β-catenin signaling pathway. PF-573228 specifically inhibits CPZ-mediated GC cell proliferation and tumor growth in mouse models (approximately fivefold compared to the control group).

This study highlights the potential of CPZ as a novel biomarker and prognostic predictor for GC, while also elucidating its role in GC progression. The identification of PF-573228 as a specific inhibitor of CPZ provides a basis for the development of new therapeutic strategies for GC diagnosis and intervention.