Therapeutic potential of targeting the NEDD4L-eEF1A1 axis in cancer therapy.

Abstract

Abnormal proliferation and migration of endothelial cells are key contributors to tumor angiogenesis. Recent studies have shown that the crucial role of E3 ubiquitin ligase neuronal precursor cell expression developmentally downregulated 4-like (NEDD4L) in tumorigenesis. However, the precise mechanisms by which NEDD4L functions in endothelial cells remain unclear. In this study, we investigate the mechanisms by which NEDD4L influences the function of human umbilical vein endothelial cells (HUVECs) and its effect on tumor angiogenesis. Our results show that NEDD4L overexpression in HUVECs suppresses both cell proliferation and migration. Additionally, we find that the autophagic activity in NEDD4L-overexpressing cells is increased. Proteomic profiling and ubiquitination assays reveal that NEDD4L interacts with eEF1A1, promoting K48-linked ubiquitination-mediated degradation of eEF1A1. This post-translational modification is a key step in the NEDD4L-mediated regulation of autophagy and cellular function. Moreover, we find that loss of endothelial NEDD4L significantly enhances tumor growth and promotes angiogenesis in vivo. Overall, NEDD4L plays a crucial role in inhibiting tumor angiogenesis by regulating eEF1A1 ubiquitination and degradation, providing new insights into the NEDD4L-eEF1A1 axis and its potential as a therapeutic target.