PAK1-RAF-Cox-2 Signaling: Essential for Cancer and Inflammation

It has been discussed previously that the kinase PAK1 is essential for both
the growth of more than 70% of human cancers and inflammatory diseases such
as asthma and arthritis. Thus, anti-PAK1 drugs (synthetic or natural) such
as FK228 and propolis would be useful for the therapy of these formidable
diseases.

Interestingly, it has been reported recently that an enzyme called COX-2
(cyclooxygenase-2) is also required for both cancer growth and inflammation.
Furthermore, OSU-03012, a derivative of the anti-Cox-2 drug "Celecoxib"
was found by Matt Ringel's group at OSU in 2007 to inhibit directly PAK1.
So I wonder if PAK1 and Cox-2 are somehow closely linked in the regulation
of both cancer growth and inflammation.

In this context, it should be noted that several anti-PAK1 products such
as FK228, CAPE, curcumin, resveratrol, capsaicin, berberine, Ivermectin,
DPM (dipyridamole), PP1 and OSU-03012 have been reported previously
to block the expression of Cox-2 gene, strongly suggesting the possibility
that PAK1 acts up-stream of this gene.

It is well known that the oncogenic RAS activates both the kinase PAK1 and
Cox-2 gene. Is PAK1 essential for the RAS-induced activation of Cox-2 gene?
YES, in 2008 Lee Slice's group at UCLA found that activation of Cox-2 gene
indeed requires PAK1, as a dominant negative mutant of PAK1 blocks the Cox-2
gene expression, and a constitutively active mutant of PAK1 alone can activate
Cox-2 gene (see below):

Hung Phama, Romina Vincentia and Lee Slice (2008)
COX-2 promoter activation by AT1R-Gq-PAK-p38 signaling in intestinal epithelial
cells.
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
1779, 408-413.

What does Cox-2? It is an enzyme that produces a group of hormones called
prostaglandins (PGs) from a fatty acid called arachidonic acid. PGs causes
contraction of smooth muscles such as those in blood vessel and uterus,
and inflammation associated with aching joints, arthritis and asthma. Around
1971, John Vane's group in London discovered that Aspirin and many other
NSAIDs (non-steroidal anti-inflammatory drugs) block the production of PGs
by inhibiting cyclooxygenases such as Cox-2. In 1982, for this historical
discovery of theirs, they shared a Nobel prize in physiology and medicine.
Thus, Cox-2 inhibitors such as Aspirin and celecoxib as well as anti-PAK1
products such as FK228 and propolis suppress pain, fever and inflammation,
in addition to the growth of cancers.

How can PGs cause cancers? RAS activates Cox-2 gene through PAK1 and Raf, and in
turn Cox-2 derived PGs such as PGE(2) constitutively activates PAS, and
eventually activates PAK1 and Raf.
In other words, RAS, PAK1, Raf and COX-2 form a highly vicious oncogenic cycle.

Now I am very curious to know if Aspirin inactivates PAK1 or Raf. Like many other
NSAIDs such as Sulindac Sulfide, Aspirin blocks both cancer growth and inflammation, and inactivates
Cox-2 gene. Furthermore, it suppresses both angiogenesis and matastasis
of cancers. These anti-cancer properties appears to be among the typical
"finger-print" properties of anti-PAK1/anti-Raf drugs.

To our great surprise, like Sulindac Sulfide (5 micro M), Aspirin (500 micro M) directly blocks the RAS-Raf interaction and inactivates the kinase PAK1,
according to the recent paper from Wen-Chun Hung's group in Taiwan (see below):

Mei-Ren Pan, Hui-Chiu Chang and Wen-Chun Hung (2008)

Non-steroidal anti-inflammatory drugs (NSAIDs) suppress the ERK signaling
pathway via block of Ras/c-Raf interaction and activation of MAP kinase
phosphatases.

Cellular Signalling, 20, 1134-1141.

To be continued