FIGURE 10.

Schematic overview of relationships between the ER stress pathway, autophagy, and NDRG1. Stress stimuli are known to lead to the phosphorylation of PERK and its downstream effector eIF2α, which can lead to autophagic initiation through phagophore formation. This latter process involves the conversion of LC3-I into LC3-II and its incorporation into the phagophore membrane (27). Iron chelators can increase expression of the metastasis suppressor NDRG1 through HIF1α-dependent and -independent pathways (14, 36). The current study demonstrates that NDRG1 suppresses LC3-II expression and the formation of autophagosomes containing this latter protein. It also demonstrated that NDRG1 increases the susceptibility of the cell toward apoptosis. Thus, it is hypothesized that the NDRG1-mediated decrease in the autophagic flux results in decreased nutrient recycling that could play a role in the ability of NDRG1 to enhance apoptosis and inhibit metastasis.