Scientists have cracked a
cell mechanism that drives tumor formation in most types of cancer. This
finding could lead to much-needed new therapies for cancer, including the
hard-to-treat triple-negative breast cancer.
The discovery concerns the
molecular activity of the tumor suppressor protein p53. This protein sits inside
the nucleus of the cell and protects the cell's DNA from stress. It has
acquired the nickname "guardian of the genome" for this reason.
However,
mutated forms of p53, which are common in cancer, behave differently than
regular p53. Instead of protecting the cell, they can take on oncogenic, or
tumor-promoting, properties and become active drivers of cancer.
Previous studies had already
shown that p53 mutations are more stable than their nonmutant counterparts and
can accumulate until they eclipse them in the nucleus. However, the mechanism
behind the stability of p53 mutations remained unclear.
Now, researchers from the
School of Medicine and Public Health at the University of Wisconsin-Madison
have unpicked the stabilizing mechanism, and they suggest that it offers a
promising target for new cancer treatments.
Their findings feature in
the journal Nature Cell Biology.
The stabilizing process
involves two molecules: the enzyme PIPK1-alpha and its "lipid
messenger" PIP2. Between them, they appear to regulate the function of
p53.
"Although p53 is one of
the most commonly mutated genes in cancer," says co-lead researcher and
study author Vincent L. Cryns, who is a professor of medicine, "we still do
not have any drugs that specifically target p53."
'Guardian of the genome'
The p53 protein protects the
genome in several ways. Inside the nucleus, it binds to DNA. When ultraviolet
light, radiation, chemicals, or other agents inflict damage on DNA, p53 decides whetherto repair the damage or
instruct the cell to self-destruct.
If the decision is to repair
the DNA, p53 triggers other genes to start this process. If the DNA is beyond
repair, p53 stops the cell from dividing and sends a signal to begin apoptosis,
which is a type of programmed cell death.
In this way,
nonmutant p53 prevents cells with damaged DNA from dividing and potentially
growing into cancerous tumors.
However, many mutant forms
of p53 involve a change to a single building block, or amino acid, in the
protein molecule, which prevents it from stopping the replication of cells with
damaged DNA.
Using a range of cell
cultures, the team behind the new study discovered that the PIPK1-alpha enzyme
links up with p53 to make PIP2 when cells become stressed due to DNA damage or
another cause.
PIP2 also binds strongly to
p53 and causes the protein to associate with "small heat shock
proteins." It is this association with heat shock proteins that stabilizes
mutant p53 and allows it to promote cancer.
"Small heat shock
proteins are really good at stabilizing proteins," Prof. Cryns explains.
"In our case, their
binding to mutant p53 likely facilitates its cancer-promoting actions,
something we are actively exploring," he adds.
Targeting p53 to fight
cancer
The scientists were
surprised to find PIPK1-alpha and PIP2 in the nucleus of cells, as these two
molecules tend to occur only in cell walls.
They also found that
disrupting the PIP2 pathway prevented the accumulation of mutant p53,
effectively stopping it from promoting tumor development.
The team suggests that
getting rid of mutant p53 could be a powerful way to fight cancers in which it
is the key driver.
This could be a promising
route for discovering drugs to treat triple negative breast cancer, an aggressive type which, by its nature, has few other drivers for drugs to
target.
The researchers are already
trawling for compounds that block PIPK1-alpha and could become candidate drugs
for the treatment of tumors with mutant p53.
"Our discovery of this new
molecular complex points to several different ways to target p53 for
destruction, including blocking [PIPK1-alpha] or other molecules that bind to
p53."
Prof. Vincent
L. Cryns
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