Abstract 3245: The Golgi protein GLG1 participates in tumor progression

Abstract

Abstract Increasing evidence suggests that endocytosis and membrane trafficking are deregulated in cancer cells. Because of their dependence on selected signaling pathways, tumor cells may need to rely on accelerated receptor recycling and increased secretion of a variety of molecules such as matrix components, adhesion molecules and growth factors. Mass spectrometry analysis of proteins associated with separase, recently shown to be an important regulator of membrane trafficking, identified the Golgi apparatus protein 1 (GLG1). GLG1 is primarily known as an E-selectin ligand that mediates the initial step of tethering and rolling of leukocytes on vascular endothelium. We therefore addressed the possibility that GLG1 could play a similar role in circulating tumor cells, facilitating arrest and extravasation into adjacent tissues. Consistent with this possibility, tail vein injection of stably GLG1-depleted tumor cells into NOD/SCID mice resulted in reduced numbers of metastatic nodules. Moreover, metastatic tumor growth was almost exclusively intravascular, indicating impaired extravasation of tumor cells. Further investigation, however, showed that, in tumor cells, GLG1 is almost exclusively localized to the Golgi apparatus, challenging the notion that it plays a direct role in mediating tumor cell adhesion to endothelium as in leukocytes. To elucidate the molecular mechanisms by which GLG1 could affect tumor cell migration through interactions at the Golgi level, we conducted experiments using GLG1-depleted human tumor cell lines. Transient silencing of GLG1 by siRNA was observed to modify cell shape (elongated morphology), to markedly alter Golgi architecture, to inhibit migration of a range of tumor cell lines, and to decrease β1 integrin protein level and impair its internalization/recycling. In addition, subsequent experiments led to the identification of BIG1, an Arf-GEF required to initiate membrane vesicle formation by promoting guanine-nucleotide exchange on Arf1 and Arf3, as a new interactor of GLG1. Taken together, our observations provide insight into a novel and specific role of GLG1 in tumor progression by affecting, thanks to its privileged position in the secretory pathway, trafficking of key molecules implicated in cell migration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3245. doi:1538-7445.AM2012-3245