Molecular Regulators of Stemness and Drug Resistance in Prostate Cancer: Roles of MUC1‑C, TMPRSS4, TLX, and MDA‑9/Syntenin

Prostate cancer (PCa) remains one of the most prevalent malignancies in men and a leading cause of cancer-related mortality, particularly in its castration-resistant and metastatic forms. Accumulating evidence highlights the central role of cancer stem cells (CSCs) in tumor initiation, progression, intratumoral heterogeneity, and the resistance to therapy and radiation. This review summarizes current data and provides an in-depth analysis of four promossing regulators of CSC-associated stemness and cellular plasticity: the oncoprotein MUC1-C, the type II transmembrane serine protease TMPRSS4, the orphan nuclear receptor TLX, and the PDZ-domain adaptor protein MDA-9/Syntenin. For each molecule, we discuss structural features, expression patterns in prostate tissue, and involvement in key oncogenic signaling pathways, including Wnt/β-catenin, PI3K/AKT, MAPK, STAT3, NOTCH, and TGF-β. Their contributions to epithelial-mesenchymal transition (EMT), maintenance of the CSC phenotype, androgen-independent growth, and resistance to standard therapies are examined in detail. Particular emphasis is placed on in vitro and in vivo evidence demonstrating the significance of MUC1-C, TMPRSS4, TLX, and MDA-9/syntenin as biomarkers of aggressive PCa and as targets for precision therapeutics and immunotherapy.

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