Role of Neuraminidase-1 in Cancer Development and Clinical Implications
The abnormal expression of cell surface sialic acid has recently been identified as an important trait of cancer cells. The main sialylation-modifying enzyme in mammalian cells, neuraminidase-1 (Neu1), has been shown to positively regulate several receptors and their activation, including the epidermal growth factor receptor (EGFR), insulin receptor (IR), and a number of TOLL-like receptors (TLR). Notably, these receptors each play unique and profound roles in tumor development and progression via promotion of cell proliferation and survival pathways, cell growth and metabolism, and immune-mediated tumorigenesis, respectively. Here, we further characterize the role of Neu1 in cancer cell signaling, as well as tumor growth, neovascularization and metastasis. Furthermore, the molecular targeting of Neu1 using competitive inhibitor and sialic acid analog oseltamivir phosphate (OP) has been evaluated for its therapeutic role in suppressing tumor progression. This report uncovers the molecular mechanisms that regulate the role of Neu1 sialidase in insulin receptor activation. Specifically, we show that GPCR agonists bombesin, bradykinin, angiotensin I and angiotensin II can stimulate Neu1 sialidase activity to induce IR activation (phosphorylation) in the absence of insulin. Furthermore, this effect can be blocked by GPCR inhibitor BIM-23127 as well as OP. The studies in this report also investigated the effect of OP in murine models of human triple-negative breast cancer (MDA-MB-231), ovarian endometrial cancer (A2780), and pancreatic ductal adenocarcinoma (PANC1) tumor xenografts growing in RAGxCγ mice. In comparison to untreated groups, OP treatment resulted in a significant reduction in tumor volume, metastatic spread to the mouse liver and lungs, as well as a reduction in tumor-associated neovascularization and recruitment of host endothelial cells. In conclusion, these findings provide insight into the novel targeting of tumor-promoting pathways via Neu1 sialidase and implicate OP as a novel agent in cancer therapy.