Heat shock proteins are co-opted for cancer
CAMBRIDGE, Mass. (Sept. 20, 2007) – A Jekyll-Hyde mechanism
that both protects healthy cells and enables cancer cells
could be the basis for new cancer-fighting drugs.
Scientists in the laboratory of Whitehead Member Susan
Lindquist have discovered that a certain transcription
factor—a protein that binds to specific areas of the genome
and acts to switch genes on and off—known to aid in handling
stresses also facilitates the survival of cancer cells.
According to the study, which appears online in
Cell on Sept. 20, this transcription factor may be
the basis for powerful new ways to fight cancer.
“We propose that HSF1 could provide a uniquely
effective target for the discovery of broadly active
anticancer agents,” says Whitehead Member Susan Lindquist. |
The transcription factor is the master regulator of cells’
protective “heat-shock” response—a complex and multifaceted
defense system that kicks in when an organism is exposed to
increased temperature, infection, toxins or other stresses.
The heat-shock response is thought to have existed for more
than a billion years and is found in organisms from bacteria
to fruit flies to humans.
Heat-shock transcription factors turn on genes for helpful
“chaperone” proteins that help keep proteins from going bad.
If proteins form unhealthy clumps, heat-shock proteins (HSPs)
pull them apart. If proteins misfold, HSPs help them refold.
If the errant proteins are too far gone, HSPs ship them
off to be destroyed.
Postdoctoral associate Chengkai Dai and his colleagues
looked at the role of heat-shock factor 1 (HSF1), the master
regulator of the heat-shock response, in enabling normal
cells to turn into cancer cells.
“This work provides the first direct evidence of an important
role for HSF1 in helping cells to undergo a malignant
transformation,” says co-author Luke Whitesell,
a research scientist in the Lindquist lab.
While the transcription factor does not itself cause
the transformation of a normal cell into a cancer cell,
it orchestrates a network of core functions in the
cancer cells that govern their proliferation, survival,
protein synthesis and metabolism.
In mice, an HSF1 deficiency drastically limited
tumor formation induced by either a chemical carcinogen
or a cancer-causing genetic mutation.
Using cells from a variety of human tumors, Dai
showed that depriving the cancer cells of HSF1
strongly suppressed their ability to grow and survive.
“We propose that HSF1 could provide a uniquely
effective target for the discovery of broadly
active anticancer agents,” says Lindquist, who is also a professor of biology at MIT and a Howard Hughes Medical Institute investigator.
It’s increasingly apparent, Whitesell comments,
that many biological mechanisms can play dual
roles—sometimes beneficial, sometimes not.
“It makes perfect sense to us that HSF1 plays
this dual role,” Dai says. “It has been shown that
HSF1 is involved in protecting against neurodegeneration,
in which brain cells die slowly over time. In cancer,
the opposite is true: cancer cells don’t die. Ironically,
cancer cells hijack and exploit this evolutionarily
conserved self-protective function of HSF1.”
In fact, he says, cancer cells appear much more
sensitive than normal cells to the loss of HSF1 function.
“It will be interesting to see how the insights gained
from studies such as this one can be applied to develop
useful therapeutics,” Whitesell says. The next step is to
look for existing compounds that induce or inhibit the
heat-shock response in cells. The challenge will be to
manipulate the target for therapeutic advantage without
tipping the scales too much or in the wrong places.
This work was supported by the G. Harold and Leila
Y. Mathers Foundation, the Children’s Tumor Foundation
and the Radcliffe Institute for Advanced Study.
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