Dickkopf-related protein 3 (Dkk-3) (DKK3)

Dickkopf-related protein 3 (Dkk-3), also known as Reduced Expression in Immortalized Cells (REIC), is a secreted glycoprotein and a member of the Dickkopf family. While its role in Wnt signaling is context-dependent, it is primarily recognized as a tumor suppressor that is frequently silenced in various cancers through promoter hypermethylation (UniProt P57735; Veeck & Dahl, 2012). The therapeutic approach mentioned involves the adenoviral delivery of the REIC/Dkk-3 gene (Ad-REIC) to restore protein levels within the tumor microenvironment. This overexpression induces apoptosis specifically in malignant cells by triggering prolonged endoplasmic reticulum (ER) stress and activating the c-Jun N-terminal kinase (JNK) pathway (Abarzua et al., 2005; Kumon et al., 2016). Beyond direct cytotoxicity, Dkk-3/REIC acts as a cytokine-like molecule that enhances anti-tumor immunity by promoting the maturation of dendritic cells and the production of interleukin-12 (Watanabe et al., 2009). Importantly, the pro-apoptotic effect of REIC/Dkk-3 overexpression appears to be selective for cancer cells, with minimal toxicity observed in normal cells, making it an attractive candidate for targeted gene therapy (Abarzua et al., 2005). Clinical investigations, particularly in prostate cancer and mesothelioma, have demonstrated that this gene therapy can induce both local tumor regression and systemic immune-mediated effects (Kumon et al., 2016; Momota et al., 2016).

Other names

REICReduced Expression in Immortalized CellsDickkopf-3RIG-7

Adenoviral-mediated delivery of the REIC/Dkk-3 gene leads to intracellular overexpression of the Dkk-3 protein, which triggers endoplasmic reticulum (ER) stress-mediated apoptosis via the JNK pathway and stimulates a systemic anti-tumor immune response through dendritic cell activation (Abarzua et al., 2005; Watanabe et al., 2009).