Dictamnine Inhibits WNT Pathway and EMT Progression in Prostate Cancer and Remodels the Tumor Microenvironment

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Prostate cancer remains a significant health concern with a need for novel therapeutic strategies.
• The Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT) are critical in prostate cancer progression.
• Modulating the tumor microenvironment is a key approach in developing effective cancer treatments.

Purpose of the Study:

• To investigate the anti-prostate cancer mechanisms of dictamnine (DIC).
• To elucidate DIC's role in reversing EMT through DKK1-mediated Wnt/β-catenin inhibition.
• To assess DIC's impact on the tumor microenvironment.

Main Methods:

• In vitro assays (CCK-8, colony formation, EdU, wound healing, Transwell) assessed cell behavior.
• Transcriptomics, bioinformatics, molecular docking, and co-immunoprecipitation identified and validated key targets.
• Western blot, gain/loss-of-function, rescue experiments, xenograft models, and immunohistochemistry were employed for validation.

Main Results:

• DIC suppressed prostate cancer cell viability, proliferation, migration, and invasion in a dose-dependent manner.
• DIC directly binds and stabilizes DKK1, enhancing its interaction with LRP6, thereby inhibiting Wnt/β-catenin signaling and reversing EMT.
• DIC independently suppressed angiogenesis and modulated tumor microenvironment factors (VEGF-A, MMP-9, IL-11, CXCL-12) and immune cell infiltration.

Conclusions:

• Dictamnine (DIC) exhibits potent anti-prostate cancer activity by targeting DKK1 to inhibit Wnt/β-catenin signaling and EMT.
• DIC demonstrates a multi-level therapeutic mechanism, including independent suppression of angiogenesis and remodeling of the tumor immune microenvironment.
• DIC represents a promising lead compound for the development of novel prostate cancer therapies.