An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications

• Published in: Cell death and differentiation 2024-07, Vol.31 (7), p.844-854
• Main Authors: De Florian Fania, Rossella, Bellazzo, Arianna, Collavin, Licio
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/1244; 631/80; AKT protein; Androgen receptors; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cancer; Cancer therapies; Cell Biology; Cell Cycle Analysis; Disabled-2 protein; DNA methylation; Down-regulation; Growth factors; Humans; Inflammation; Life Sciences; Metastases; miRNA; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; NF-κB protein; Post-transcription; Protein interaction; Proteins; ras GTPase-Activating Proteins - genetics; ras GTPase-Activating Proteins - metabolism; Review Article; Signal Transduction; Stem Cells; Stromal cells; Tumor microenvironment; Wnt protein; β-Catenin
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-024-01332-3

The dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting protein) plays an important role in this context, since it modulates cell responses to multiple extracellular inputs, including inflammatory cytokines and growth factors. DAB2IP is a RasGAP and negatively controls Ras-dependent mitogenic signals. In addition, it modulates other major oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptor signaling. In line with its tumor-suppressive role, DAB2IP is frequently inactivated in cancer by transcriptional and post-transcriptional mechanisms, including promoter methylation, microRNA-mediated downregulation, and protein-protein interactions. Intriguingly, some observations suggest that downregulation of DAB2IP in cells of the tumor stroma could foster establishment of a pro-metastatic microenvironment. This review summarizes recent insights into the tumor-suppressive functions of DAB2IP and the consequences of its inactivation in cancer. In particular, we explore potential approaches aimed at reactivating DAB2IP, or augmenting its expression levels, as a novel strategy in cancer treatment. We suggest that reactivation or upregulation of DAB2IP would concurrently attenuate multiple oncogenic pathways in both cancer cells and the tumor microenvironment, with implications for improved treatment of a broad spectrum of tumors.