Annexin A1: FK228-induced Suppressor of both Cancer and Inflammation.

Annexin is a family of proteins which bind negatively charged lipids such
as phospholipids in the plasma membranes in a Ca-dependent manner. The first
member of this family (called "synexin") was discovered in 1977 by Harvey
Pollard's group at NIH. Annexin family of over 160 different proteins is
involved in a wide variety of cell physiology in general, depending on each
member. Some of them appear to form a Ca ion channel.

Annexin A1 antagonizes PAK1

Annexin A1 (also called " Lipocortin-1") is involved mainly in both promoting
apoptosis (programmed cell death)/growth arrest and blocking inflammation.
According to the 2003 report from Egle Solito's group of Imperial College
London, the annexin causes the apoptosis of PMN (polymorphonuclear) neutrophils
by Ca-dependent dephosphorylation (activation) of pro-apoptotic BAD. Also
the annexin down-regulates cyclin D1, leading to the growth arrest. In other
words the annexin blocks both up-regulation of cyclin D1 and phosphorylation
(inactivation ) of BAD which are mediated by the oncogenic kinase PAK1.
Thus, clearly the annexin shuts down the PAK1 signaling.

Interestingly, annexin A1 gene was recently found by Marina Konopleva's
group at MD Anderson Cancer Center to be activated by a ring peptide called
FK228. FK228 is so far the most potent anti-cancer drug which blocks PAK1
by inhibiting HDAC (histone deacetylase), though this drug is not available
on the market as yet (currently at phase 2 of sluggish clinical trials mainly
for CTCL, cutaneous T-cell lymphoma).

FK228 is both anti-cancerous and anti-inflammatory

This drug is known to activate a specific set of several tumor suppressor
genes such as p21 (a CDK inhibitor) and Rap1 (a RAS antagonist). p21 causes
the growth arrest of cancer cells by inhibiting CDK (cyclin dependent kinase)
. The GTPase Rap1 could block the activation of PAK1 by blocking the interaction
of oncogenic RAS and PI-3 kinase, eventually causing both growth arrest
and apoptosis of cancer cells, and also blocking their metastasis and angiogenesis.


Interestingly FK228 is known to suppress the inflammatory diseases such
as arthritis and asthma in mouse/rat models, in addition to blocking the
malignant growth of tumor cells. How does this drug block the inflammation?
I believe that FK228-induced activation of Annexin A1 gene could explain
the reason why. For Annexin A1 is known to block the inflammation. Also Annexin
A1 appears to be responsible in part for FK228-induced apoptosis and growth
arrest.

MIR-196a inactivates Annexin A1 gene

More recently, an oncogenic micro RNA called MIR-196a was shown, by another
group led by Dr. R. Luthra at MD Anderson Cancer Center, to down-regulate
Annexin A1 gene. Thus, it is likely that MIR-196a could cause the inflammation,
in addition to the development of cancers. This close relationship between
cancer and inflammation appears to be strengthened by the fact that CAPE
(caffeic acid phenethyl ester) and ARC (artepillin C), the major anti-cancer
ingredients in propolis extracts such as Bio 30 and GPE (Brazilian green
propolis extract), respectively, could suppress the inflammation as well.
These propolis extracts, now available on the market, have been widely
used for the treatment of both cancer and inflammation.

So I wonder if CAPE and ARC also activate Annexin A1 gene or suppress MIR-196a
gene. Both CAPE and ARC selectively block the oncogenic PAK1 signaling pathways
as does FK228. These findings further suggest a possibility that PAK1 might
be involved in the inflammatory reactions such as the activation of PMN
neutrophils, in addition to the oncogenicity.

Continued