WIF1 and DKK3 in prostate cancer: from molecular pathways to therapeutic targets: a narrative review.

Abstract

Listen

Translate article

Prostate cancer is a major cause of cancer-related morbidity and mortality in men globally. The pathogenesis involves complex interactions between genetic mutations and environmental factors, activating multiple signaling pathways, especially Wnt/β-catenin, PI3K/Akt, and NF-κB pathways. Tumor suppressor genes WIF1 and DKK3 are key inhibitors of these pathways, crucial in suppressing tumor growth and metastasis. This review synthesizes current knowledge on WIF1 and DKK3 in prostate cancer, focusing on their biological functions, regulatory mechanisms, and therapeutic potential. A comprehensive literature review was conducted, examining studies on the molecular biology of WIF1 and DKK3, their expression in prostate cancer, and their impact on processes like proliferation, apoptosis, migration, and invasion. WIF1: (I) Inhibition of Wnt/β-catenin signaling: WIF1 binds to Wnt ligands, preventing receptor interaction and reducing c-Myc and Cyclin D1 expression. (II) Promotion of apoptosis: WIF1 downregulates anti-apoptotic proteins (e.g., Bcl-2) and upregulates pro-apoptotic proteins (e.g., Bax), promoting both intrinsic and extrinsic apoptotic pathways. (III) Suppression of epithelial-mesenchymal transition (EMT) and metastasis: WIF1 inhibits EMT, reduces cell migration, and modulates matrix metalloproteinases (MMPs) to maintain extracellular matrix (ECM) integrity. DKK3: (I) Regulation of signaling pathways: DKK3 modulates Wnt/β-catenin, PI3K/Akt, and NF-κB pathways, reducing cell proliferation. (II) Enhancement of apoptosis: DKK3 increases p53 activity and upregulates PUMA and NOXA while reducing apoptosis inhibitors. (III) Inhibition of cell migration and invasion: DKK3 suppresses EMT, cytoskeletal dynamics proteins like RhoA and Cdc42, and reduces MMPs, limiting invasiveness. The tumor suppressor functions of WIF1 and DKK3 are critical in the context of prostate cancer. Their ability to inhibit key signaling pathways and promote apoptosis highlights their potential as therapeutic targets. Future research should focus on developing strategies to restore their expression and function, including epigenetic therapies, gene therapy, and small molecule inhibitors. Such approaches could significantly enhance the efficacy of existing treatments and improve patient outcomes.