Sortilin mediates the release and transfer of exosomes in human lung cancer A549 cells

Abstract

The transfer of exosomes containing both genetic and protein materials is necessary for the control of cancer cell microenvironment to promote tumor angiogenesis. The nature and function of proteins found in the exosomal cargo, their mechanisms in membrane transport and related signaling events are not clearly understood. The multifaceted receptor, neurotensin (NT) receptor-3, also called sortilin plays a multitude of roles in the cell as a receptor or a co-receptor, in protein transport to the plasma membrane and to lysosomes, and in the regulated secretion. Numerous studies indicate that sortilin expression is elevated in several human cancers. These same reports suggested that NT mediated by sortilin stimulated by an autocrine/paracrine function could be a mechanism associated with the tumorigenesis. In this study, we demonstrate in human lung cancer A549 cells, that the exosome release mechanism is closely linked to a multifaceted receptor, neurotensin (NT) receptor-3 also called sortilin. Sortilin is already known to be important for cancer cell function. We report for the first time its role in the assembly of a tyrosine kinase complex and subsequent exosome release. This novel complex (TES complex) found in exosomes results in the linkage of two tyrosine kinase receptors, TrkB and EGFR with sortilin. Using in vitro models, we demonstrate that this complex containing sortilin exhibits a control on endothelial cells and angiogenesis activation through exosome transfer. We show for the first time, a new role for sortilin in the release and the assembly TES complex in lung cancer cells. Our data suggest a paracrine function for sortilin and its partners in exosome transfer and the control of the microenvironment. This novel complex containing sortilin could act as a molecular switch in cancer progression by promoting angiogenesis.