KAI1 (CD82) Suppresses Metastasis, Cell Proliferation and Invasion - Therapeutic Strategies in Cancer Biology and Pathology - page 78

P53 ↑ KAI1/CD82 ↑ ← ← NDRG1

↓

VEGF

ER HIF1 HGFEGF / EGFR

↑

Fulvestran

Metastasis/cell proliferation/invasion

Figure 13.1 Postulated routes of suppression of metastasis, cell proliferation and motility
by KAI1. Also shown are some interacting genes such as the suppressor p53 and NDRG1.
NDRG1 can inhibit the metastasis promoting transcription factor ATF3. Further details
of HGF signalling are shown in Figure 13.2 and the effects of KAI1 on that pathway are
described in legend to that figure and also in the text.

HGF

c-met PKC signalling PI3K/Akt/mTOR

PI3K/FAK

β -Catenin Ras/Raf/MEK/ERK PI3K/Akt RhoGTPases/

activation Rho/Rac/cdc42

mTOR

Rac

Cell survival Cell motility

Figure 13.2 The potential pathways HGF mediated effects on cell survival and motility
regulated by HGF. KAI1 might affect signalling involved with both cell proliferation and
survival, but there are also suggestions that it can selectively inhibit Rho GTPases/Rho/Rac/
cdc42 signalling cell motility.

expression. Unfortunately, no attempt has been made to quantify angiogenesis
in vivo . Nonetheless, inhibition of angiogenesis is an assured mode of modulating
metastasis.
The p53 protein is said to directly activate the KAI1 gene by interacting with its
promoter via a consensus-binding sequence (Mashimo et al., 1998). Loss of both p53
and KAI1 has been associated with poor survival in prostate cancer. These findings
assume great importance with p53 being mutated in a large majority of human neo-
plasms and in the context of their relevance to the deregulation of cell proliferation.
It would be relevant to cite here the work of Christgen et al. (2008) who noticed a
link between KAI1 expression and the expression of ER. ER positivity closely cor-
related with loss of KAI1. KAI1 transcription showed a far greater downregulation
in ER-positive than in ER-negative tumours. These effects were suppressed by ER
antagonists accompanied by KAI1 upregulation and inhibition of cell proliferation
and motility.