Johns Hopkins researchers have discovered a previously
unsuspected mechanism of cell death that may afford a new
way to find and develop stronger yet less-harmful anticancer
drugs. Specifically, they have found that a cellular
stress-response protein prevents cells from dying by
interacting with a particular signaling protein and mediating
its response to some conventional anticancer drugs. The
results appear in the Jan. 14 Early Edition of the
Proceedings of the National Academy of Sciences.
"A major hang-up in cancer chemotherapy is the toxicity
caused by DNA disruption of cell division throughout the
body. Our research suggests that drugs like cisplatin and
novobiocin kill cells as much from this newly discovered
mechanism as any other mechanism of cell death," said
Solomon H. Snyder, Distinguished Service Professor of
Pharmacology and Psychiatry at Johns Hopkins. "Targeting
this new mechanism in drug design might make for therapies
with fewer side effects."
Snyder and colleagues previously had discovered that cell
stressors, including anticancer drugs, rapidly activate the
protein IP6K2, which promotes cell death. The team searched
for proteins that bind to and potentially control IP6K2 and
found a heat shock protein, HSP90.
"This was really interesting because HSP90 is a survival
protein," Snyder said. "On the one hand, we have IP6K2,
which is pro-death, and on the other, we have the pro-life
HSP90, so we thought maybe they might be duking it out in a
When the researchers looked more closely at the interactions
between HSP90 and IP6K2, they found that when the two are
bound to each other, IP6K2 stops working. When the
researchers altered IP6K2 so that it couldn't bind to HSP90,
they were able to restore IP6K2 function. And presumably,
according to Snyder, the cell would die.
The team then asked whether the anticancer drugs cisplatin
and novobiocin, which cause cell death, somehow interfered
with HSP90-IP6K2 interactions. The scientists found that at
normal, therapeutic doses, both drugs did block the two
proteins from binding, enabling IP6K2 to function
According to Snyder, HSP90 normally binds to IP6K2 and
prevents cell death. But the drugs cisplatin and novobiocin
can bind to HSP90 and cause it to let go of IP6K2, freeing
IP6K2 to promote cell death.
"Our findings could be applied to design new anticancer drugs
that specifically block this HSP90-IP6K2 interaction. These
drugs may be more selective and therefore have fewer side
effects than classical chemotherapeutic agents, which can
cause all sorts of DNA damage," Snyder said.
The research was funded by a U.S. Public Health Service grant
and research scientist award.
Authors on the paper are Anutosh Chakraborty, Michael
Koldobskiy, Katherine Sixt, Krishna Juluri, Asif Mustafa,
Adele Snowman, Damian van Rossum, Randen Patterson and
Snyder, all of Johns Hopkins.