Suppressor Function of NDRG1 - Therapeutic Strategies in Cancer Biology and Pathology - page 97

Fe chelators uteolin DNA damage

BTG2
Maspin

HIF-1 Ets P53

C-myc NO

ATF3 ← C-myc

MMP NDRG1 ↑

Oestradiol Akt

PTEN Wnt/ β -catenin

Invasion Cell proliferation Angiogenesis EMT

Figure 15.1 The several pathways by which NDRG1 exerts its inhibitory effects on invasion,
cell proliferation, EMT and also possibly angiogenesis and so inhibit metastatic spread
(discussed in detail in the text).

NDRG1 Suppresses MMP Activity and Invasion

There is a large body of evidence supporting the view that NDRG1 actively suppresses
migration and cell proliferation, but the precise mechanisms involved in the genera-
tion of these biological effects have not been investigated. In gene transfer, NDRG1
exerts marked inhibitory effects on cell migration in vitro , which have been ascribed
to reduced expression of MMP-9 (Maruyama et al., 2006). Human gastric adenocarci-
noma cells in which NDRG1 was suppressed using siRNA showed enhanced in vitro
migration and gelatinolytic activity due to MMP-2/MT1-MMP (membrane type 1
MMP), but when NDRG1 expression was restored, the cells lost the acquired invasive
ability (Liu et al., 2011f). One would recall here that MT1-MMP is a transmembrane
MMP capable of remodelling the ECM and influence cell motility.

Upregulation of NDRG1 Suppresses Cell Migration and
Proliferation

Effects of Iron Chelators
NDRG1 is upregulated by free radical NO and this suppresses cell migration (Hickok
et al., 2011). The single unpaired electron of NO enables it to bind strongly to the
iron in heme groups and other iron proteins. Hickok et al. (2011) go on to show that
free radical NO interacts with the chelatable iron pool generating complexes that
lead to NDRG1 regulation and to the inhibition of cell migration. Raising NDRG1
levels might be a mechanism by which iron chelators exert their anti-proliferative
effect. Iron chelators do indeed upregulate NDRG1 by the mediation of HIF-1
(Le and Richardson, 2004) and NO synthesis. The anti-proliferative effects of iron
chelators may occur by other mechanisms, for example p21 and cyclin D1 among
others (Richardson, 2005). Richardson et al. (2006) have described a series of di-
2-pyridyl ketone thiosemicarbazone anti-proliferative compounds which selectively