S100A4 as a Potential Target - Therapeutic Strategies in Cancer Biology and Pathology - page 63

these processes via the agency of CD44, integrins and the cadherins. Reverting to
the story of osteopontin, expression of Merlin protein, not gene transcripts, inversely
correlates with osteopontin in breast cancer. We know that Merlin inhibits PI3K/
Akt signalling. It is also known to inactivate PAK (p21-activated kinase) 1, a ser-
ine/threonine kinase that participates in the regulation of the actin cytoskeleton. On
the other hand, osteopontin has been linked with Akt-mediated phosphorylation
and degradation of Merlin (Morrow et al., 2011). Furthermore, the regulatory link
between osteopontin and Merlin is supported by the fact that CD44, which acts as an
osteopontin receptor and routes its signals downstream, is antagonistic in function to
Merlin. Either way osteopontin negates the function of Merlin and its negative regu-
lation of growth via the downstream Hippo pathway to constrain cell proliferation
and growth and promote apoptosis. So prevention of degradation of Merlin by PI3K
or by inhibition of osteopontin could be a valuable approach. To complete the picture
of the complexity of interactive signalling, it has emerged that active Merlin local-
ises Wnt/β-catenin at the cell membrane which renders the proliferative signalling by
Wnt ineffective (Zhou et al., 2011a) ( Figure 9.1 ).
Since osteopontin function is subject to regulation by Wnt, S100A4 and NF-κB,
here is provision of many options available for therapeutic intervention. The Hippo
signalling system and its components, for example the transcriptional co-activator
YAP (Yes-associated protein) and LATS2 (large tumour suppressor homolog 2) that
can inactivate YAP are also potential targets in this network of interactions.
Many studies have implicated other signalling pathways, for example Ras/ERK
and the Src kinases. At the risk of reiteration, osteopontin transcription is regulated
by a complex that includes Ets, PEA3 and β-catenin/TCF-4. Besides, the activity of
the PEA3 is accentuated by Ras-ERK signalling. Substantive proof of the operation
of these pathways in the generation of the invasive phenotype is currently awaited.
RAGE/NF- κ B Signalling in S100A4 Function
The receptor for advanced glycation end products (RAGE) has been implicated in
human pathogenetic conditions such as diabetes, atherosclerosis and Alzheimer's
disease. RAGE interacts with diverse ligands and activates NF-κB as well as binds
to integrins, thus subserves several cellular functions of promoting cell proliferation,
motility and metastasis. Quite appropriately therefore inhibition of RAGE and/or
NF-κB activation has been viewed as viable options of therapy of tumour growth and
progression.
The S100 family proteins too act as RAGE ligands. RAGE ligands interact with
Amphoterin, a 30kDa protein with HMG1-type sequence. Amphoterin is a hepa-
rin binding protein and shows particular localisation at the leading edges of motile
cells and thus shares biological features with the HMG group. The disruption of this
interaction is known to inhibit tumour growth. Kawada et al. (2010) have isolated a
natural compound (NBRI17671) from a species of the fungus Acremonium, which
is highly effective in inhibiting growth. It was also found to downregulate MAPK
suggesting the inhibition of RAGE-Amphoterin might have led to inactivation of