Biology Reference
In-Depth Information
13
KAI1 (CD82) Suppresses
Metastasis, Cell Proliferation
and Invasion
The KAI1 was identified as a metastasis suppressor gene by Dong et al. (1995), who
demonstrated that upon transfer into rat AT6.1 prostate cancer cells suppressed meta-
static spread and also that it was downregulated in metastatic prostate cancer. It is
now known to function as a suppressor in many tumour types. Over the years, much
has been learnt about the biology of KAI1 and the wide ranging influences that it
exerts are increasingly being appreciated so much so that it could be deemed now
as potential target for cancer therapy. The KAI1 gene product (CD82) is a tetras-
pan transmembrane protein. KAI1 also markedly interferes with the expression of
ECM components such as β1 integrin and fibronectin involved in intercellular adhe-
sion (Lee et al., 2011) and in this way influences cell motility and invasion. Abe
et al. (2008b) have implicated KAI1 in E-cadherin/β-catenin signalling, and with
E-cadherin closely associated cell-cell adhesion this does seem distinctly possible.
The HGF/c-met signalling system is a major activator cell migration. One should
also recall here that HGF can activate Wnt/β-catenin signalling and promote prolif-
eration (Apte et al., 2006). KAI1 has been shown to inhibit the promotion of inva-
sion by HGF (
Figures 13.1 and 13.2
). On the other hand, KAI1 could be functioning
via the agency of integrins, whose functions it does influence. Sridhar and Miranti
(2006) showed that it markedly suppressed integrin-dependent activation of c-met
and its activation by HGF. Thus it could be involved in inhibition of both migration
and cell proliferation promoting effects of HGF. HGF can activate several pathways
of signalling. Binding to c-met can activate several pathways (
Figure 13.2
). Of these,
KAI1/CD82 is said to selectively diminish Ras-Cdc42/Rac and IP3K/Cdc42/Rac
pathways, but not IP3K/Akt and PI3K/MAPK (Takahashi et al., 2007). This seems
to suggest that KAI1 selectively inhibits cell migration, not both migration and cell
proliferation. However, PI3K/Akt signalling can function through mTOR/Rac influ-
encing both cell proliferation and migration. Indeed Choi et al. (2009) found KAI1
downregulated Rac 1 expression through the PI3K/Akt/mTOR pathway. This aspect
does need further study beneficial not only from the point of view of the effective
outcome, but also from the viewpoint of possible strategic use of agents that could
function additively with KAI1.
When read in this background, the recent report concerning the inhibition of
VEGF and HIF-1 expression by KAI1 (Park et al., 2012) gains much significance.
Park et al. (2012) have described a complex pathway by which KAI1 seems to do
this, involving VHL which is known to upregulate HIF-1α that stimulates VEGF
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