RKIP Suppresses Invasion and Metastasis - Therapeutic Strategies in Cancer Biology and Pathology - page 125

Snail

NO

RKIP

E-cadherin NF-κB

IKK

Epithelial mesenchymal Apoptosis

transition Survival

Figure 22.3 The RKIP/Snail/E-cadherin mediated regulation of EMT activation and the
control of the normal NF-κB apoptosis/survival pathway by RKIP. The figure is based on
references discussed in the text.

complex consisting of the kinases IKK-α and IKK-β and the regulatory subunit IKK-γ.
RKIP inhibits both IKK-α and IKK-β and TAK1 (TGFβ-activated kinase 1), an IKK
kinase that can activate NF-κB. In this way, RKIP can lead to the inactivation of the
NF-κB cascade (Yeung et al., 2001). RKIP also interacts with TRAF6 (TNF receptor-
associated factor 6) (Chatterjee et al., 2004; Tang et al., 2010), an essential element in
NK-κB activation. As noted earlier, NF-κB is also involved with the activation of EMT
in interaction with other pathways, for example of TGF-β and Wnt signalling, and
effecting the downregulation of E-cadherin. Bonavida and Baritaki (2011) have found
that NO (nitric oxide) induces apoptosis under certain conditions and this is mediated
by its ability to upregulate RKIP expression leading to the inhibition of NF-κB, but this
can probably occur independently of NO.
The transcription factor Snail, a negative regulator of E-cadherin, is also appar-
ently involved in this regulatory loop. Snail seems able to downregulate RKIP (Wu
and Bonavida, 2009) by suppressing transcription mediated by a proximal E-box
(enhancer box palindromic motif) on the RKIP promoter (Beach et al., 2008) and
in this way promote activation of EMT. In reciprocation, RKIP can conceivably
suppress Snail (Bonavida and Baritaki, 2011) and this can result in upregulation of
E-cadherin and suppression of EMT. To insert a sub-loop, NF-κB can itself regulate
transcription of Snail.
One can visualise interaction of RKIP with Notch and Wnt signalling in influenc-
ing the activation of EMT. RKIP possesses the E-box motif in its promoter. E-boxes
are binding sites for bHLH proteins such as Notch. The Snail family zinc finger tran-
scription factors also bind to gene promoters with the E-box motif. The intracellular
domain of Notch directly engages the Snail promoter and upregulates Snail expres-
sion (Sahlgren et al., 2008). This would lead to downregulation of E-cadherin and
activation of EMT. Now GSK3-β can degrade Snail, but Wnt can suppress this activ-
ity of GSK3-β and stabilise Snail (Yook et al., 2005, 2006). Essentially this would
be a negative regulation of the function of RKIP which itself is able to downregu-
late Snail expression. Therefore in the background of RKIP, inhibition of Notch and
or Wnt would synergise with RKIP towards suppression of EMT. Ras and Notch
signalling pathways do interact but no direct interaction between RKIP and NCID
(Notch intracellular domain) has been reported ( Figure 22.3 ).