Suppressor Function of NDRG1 - Therapeutic Strategies in Cancer Biology and Pathology - page 99

Vandetanib (ZD6474) Upregulates NDRG1
Vandetanib (ZD6474) is an inhibitor of VEGFR and EGFR kinases and reason-
ably successful in clinical trials with some forms of cancer. Efficacy of this drug in
combination therapy is currently being investigated in clinical trials. Of much inter-
est here is the demonstration that this drug upregulates several hypoxia-inducible
genes, among them NDRG1. In vivo tumour models, the drug has been found to
inhibit metastasis (Arao et al., 2006). These authors did not look at the expression of
VEGFR function, so there is no suggestion that the drug inhibited metastasis by this
route.
Regulation of Cell Proliferation by NDRG1 Mediated by p53
NDRG1 appears to be associated with regulation of cell proliferation. NDRG1 might
be one of the targets of the cell cycle regulator p53 gene. HCC cells transfected with
NDRG1 show cell cycle arrest at G0/G1 (Akiba et al., 2011), indicating the involve-
ment of functional p53. Stein et al. (2004) showed some time ago that NDRG1 is
upregulated by DNA damage. DNA damage also induces p53 expression. Indeed
NDRG1 upregulation is p53-dependent. They identified a p53 binding site in the
NDRG1 promoter. Obviously here one is looking at wild-type p53 being induced
in response to DNA damage. Intriguingly, however, mutated p53 is also apparently
able to target NDRG1. Polyamine-mediated regulation of proliferation of intestinal
mucosal epithelia involves p53-induced expression of NDRG1. Polyamine deple-
tion of intestinal epithelial cells is said not only to induce p53 but also upregulate
NDRG1 expression by activating its transcription (Zhang et al., 2007). Lerner et al.
(2012) induced apoptosis of HCT-116 expressing wild-type p53 gene and Colo-320
cells carrying a mutant form of the gene by exposing the cells to 3,3′-diindolyl-
methane. Both cell lines displayed induction of apoptosis, but NDRG1 was upregu-
lated only by Colo-320 cell line that expressed mutant p53. Mutations abrogate cell
cycle control of p53, so it would seem that in these experiments the upregulation of
NDRG1 could be due to de novo transcription of wild-type p53 in response to stress
factors. There is also the possibility that stress-induced p21 might be involved here.
Indeed NDRG1 is said to upregulate p21 quite independently of p53 (Kovacevic
et al., 2011b).
Oestradiol and NDRG1 Expression
Oestradiol seems to downregulate NDRG1 expression as shown by Fotovati et al.
(2006). These authors transfected breast cancer cell lines with ERα cDNA and
generated cells expressing high or low levels of the receptor. Upon treatment with
oestradiol, those cell lines which expressed ERα at high levels showed reduced
NDRG1 expression. Fotovati et al. (2006) also found an inverse correlation between
NDRG1 and ERα expression in breast cancer samples. This is compatible with the