Abstract:
Glioblastoma multiforme (GBM) is a highly aggressive and heterogenous brain tumor classified as grade IV, with a poor prognosis and limited effective treatment options. Due to the elevated metabolic requirements of tumor cells, amino acid deprivation therapy has gained attention as a promising treatment approach. Glioblastoma exhibits a critical dependence on extracellular arginine due to the frequent loss of argininosuccinate synthetase 1 (ASS1). This study investigates the impact of arginine deprivation, induced by [HuuArgI(Co)-PEG5000], on the migration, adhesion, and invasion of A172 glioblastoma cells, and autophagy’s potential role in mediating these effects. Autophagy, a cellular recycling mechanism, serves a dual function in tumor development, either supporting cell survival or triggering cell death depending on the tumor stage and microenvironment. Our results show that arginine deprivation significantly activates autophagy in A172 cells, as evidenced by increased autophagosome formation and LC3-II/LC3-I ratios. Despite this, cell migration and adhesion were reduced, with no significant reversal detected upon adding chloroquine, an autophagic flux inhibitor. Interestingly, invasion in a 3D Matrigel model was enhanced under arginine deprivation, partially mediated through autophagy. The results suggest that while autophagy contributes to some of the observed effects, other pathways, including cytoskeletal remodeling and extracellular matrix interactions, likely play a role. These findings highlight the need for further research to elucidate the interplay between autophagy, Rho GTPases, and metastasis in glioblastoma cells.
