RKIP Suppresses Invasion and Metastasis - Therapeutic Strategies in Cancer Biology and Pathology - page 122

RKIP Inhibits Invasion and Growth of Cancer
In vitro studies show that RKIP markedly inhibits cell motility (Li et al., 2008,
2009d), accompanied in parallel by reduction of MMP-2 and MMP-9, cathepsin B
and uPA (Xinzhou et al., 2011). Beshir et al. (2010) reported the induction of inva-
sive behaviour together with enhanced expression of MMP-1 and MMP-2 resulted
from silencing of RKIP and overexpression of RKIP led to decreased invasion and
metastasis in vivo . No significance should be read into the different MMPs being
affected by RKIP. The MMPs are corporately involved in ECM remodelling. Hao
et al. (2012) have reported that RKIP transfected MDA-MB-231 cells showed
reduced cell migration and this appeared to be related to and possibly attributable to
the inhibition of MMP-1 and MMP-2. In accord with this, Xinzhou et al. (2011) and
Martinho et al. (2012) found that suppression of RKIP increased cell survival and
migration, but did not influence cell proliferation. Aside from the invasion promoting
proteases, many other molecular entities that influence motility have been implicated
in the absence of RKIP. The induction of β-catenin, vimentin, c-met receptor tyros-
ine kinase and PAK1 have been reported (Al-Mulla et al., 2011). As discussed below,
RKIP might be regulating the initiation of EMT here. Beshir et al. (2010) believe
that RKIP achieves MMP suppression by inhibiting NF-κB.
In the backdrop of the ability of checkpoint regulation and the integration of signal-
ling by RTKs and GPCRs, it is rather difficult to comprehend and appreciate why there
has been so little attention directed to the regulation of cell proliferation by RKIP or to
appreciate the divergence of view in the scanty data currently at hand. Some while ago,
Fu et al. (2003) transfected LNCaP and C4-2B cells with antisense and sense RKIP
cDNA. The transfected derivatives showed no differences in proliferation in vitro or in
colony-forming ability. According to Li et al. (2008), cell proliferation and anchorage-
independent growth are also inhibited in ovarian cancer cells that overexpressed RKIP.
Inhibition of proliferation was due to cell cycle arrest rather than to induction of apop-
tosis. But these authors found no suppression of cell proliferation in the case of breast
cancer cell lines (Li et al., 2009d). Recent reports show that restoration of expression
of epigenetically silenced RKIP by 5-azacytidine treatment and also by transfection of
RKIP has led to the inhibition of proliferation of TE-13 oesophageal squamous cell
carcinoma cells (Guo et al., 2012). Zhang et al. (2013) have shown that RKIP inhib-
ited cell cycle progression and induction of apoptosis in the gastric cancer cell line
SGC7901. RKIP also inhibited cell migration as shown by in vitro assay. Implantation
into animal hosts showed RKIP inhibited the growth of tumour xenografts. More deci-
sive evidence has recently emerged which shows that silencing of RKIP hastens G 1 -S
transition and DNA synthesis (Al-Mulla et al., 2011).
RKIP Downregulation is a Frequent Event in Cancer
RKIP is downregulated in many tumours. Loss of RKIP expression in oesophageal
dysplasia and squamous cell carcinomas was due to promoter methylation and meth-
ylation corresponded with loss of transcription and protein expression (Guo et al.,