S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 64

NF-κB. For instance, S100P promotes cell proliferation and survival by activating
ERK and NF-κB signalling. The effects of S100P were suppressed by Amphoterin-
derived peptide that inhibits RAGE activation and also by anti-RAGE antibodies, and
by expression of a dominant-negative RAGE (Aarumugam et al., 2004). Akin to this
is the observation relating to S100A4. Activation by S1004 of the NF-κB pathway
seems to involve RAGE. The induction of cell migration by S100A4 is inhibited by
the inhibition of RAGE using siRNA. This also inhibited the phosphorylation of ERK
and MMP-2 (Spiekerkoetter et al., 2009). Presumably this could suggest activation
of NF-κB by the classical course of action. Exposure of cardiac myocytes to S100β
increases VEGF mRNA and protein together with the activation of the classical
NF-κB pathway. These effects were inhibited by caffeic acid phenethyl ester (CAPE).
Myocytes expressing dominant-negative RAGE did not show induction of VEGF or
NF-κB activation indicating that S100β functioned via RAGE (Tsoporis et al., 2012).
Caffeic acid (CA) and CAPE have been investigated for their anti-tumour effects
and for inhibition of NF-κB signalling. Both were shown some time ago to inhibit
in vitro invasion and in vivo metastatic spread of HepG2 HCC cells. Concomitantly
these compounds inhibited MMP-9 activity and suppressed NF-κB signalling
(Chung et al., 2004). Although Chung et al. (2004) suggested at the time there the
biological effects resulted dual modes of MMP inhibition and inhibition of NF-κB,
we know now that the two are indeed linked. NF-κB can signal via CD44 and also
the osteopontin pathway to activate MMPs. Also as discussed earlier, the promotion
of invasion and induction of MMP expression by S100A4 is mediated by NF-κB.
Since then much progress has been made with these compounds. CAPE, a constitu-
ent of honey bee resinous product called propolis, inhibits NF-κB and activates the
transcription factor NFAT and inhibits the classical pathway by delaying IκBα deg-
radation and the translocation in to the nucleus of p65 (RelA) (Ang et al., 2009).
At the phenotypic level, CAPE inhibits cell proliferation and promotes apoptosis,
with parallel upregulation of the pro-apoptotic Bax expression and downregulation
of the anti-apoptotic Bcl-2. In vivo tumour development upon implantation of chol-
angiocarcinoma (CCH) cells into Balb/c nude mice had a longer latency and showed
growth inhibition (Onori et al., 2009). Similar growth inhibition occurs in CAPE-
treated MCF-7 and MDA-231 breast cancer cells, with supplementary inhibition of
VEGF and apparent inhibition of angiogenesis (Wu et al., 2011a). It would be worth
noting here that CAPE was shown some time ago to be a highly efficacious inhibitor
of NF-κB activation. CAPE-induced apoptosis was accompanied by the loss of IAPs
(inhibitors of apoptosis protein) cIAP-1, cIAP-2 and XIAP (McEleny et al., 2004).
Berger et al. (2007) have described another inhibitor of NF-κB, namely Bay 11-7085
which appears to be more efficient than CAPE in B-lymphoma cell lines, possibly
functioning by a different mechanism from CAPE.
Now to return to the RAGE story, the RAGE inhibitor PF-04494700 is in clini-
cal trials for the treatment of Alzheimer's disease. FPS-ZM1 is another puta-
tive RAGE-specific inhibitor that binds to the V domain of RAGE and blocks
amyloid beta-mediated murine model of the disease (Deane et al., 2012).
Yamamoto et al. (2001) reported some time ago that a putative AGE inhibitor,