The newly identified
tumor suppressor, N-myc downstream-regulated gene 2 (NDRG2), has been studied in various
cancers because of its anticancer and antimetastasis effects. In this study, we examined the effect of NDRG2 expression on cell viability in MDA-MB-231 human
breast cancer cells under conditions that are similar to the microenvironment of solid
tumors, which include
glucose deprivation. NDRG2 overexpression enhanced the pro-apoptotic effects of
glucose deprivation.
Glucose deprivation also induced the activation of
AMP-activated protein kinase (AMPK), which plays a role in protecting
tumor cells from metabolic stresses. NDRG2 overexpression strongly reduced
glucose deprivation-induced AMPK phosphorylation and increased the cleavage of
poly (ADP-ribose) polymerase (PARP), which indicated the induction of apoptosis. The expression of a constitutively active form of AMPK effectively blocked
glucose deprivation-induced apoptosis in NDRG2-overexpressing MDA-MB-231 cells. Moreover, NDRG2 overexpression also enhanced the pro-apoptotic effects of
2-deoxyglucose (2-DG) or
hypoxia, an inducer of metabolic stresses. Finally, we showed that LKB1 is an upstream
kinase of AMPK that is involved in the inhibition of
glucose deprivation-induced AMPK activity in NDRG2-overexpressing cells. Our findings collectively suggest that NDRG2 is a negative regulator of AMPK activity and functions as a sensitizer of
glucose deprivation.