Both radiation and many forms of chemotherapy try to kill tumors by causing
oxidative stress in cancer cells. New research from the University of Southern California
(USC) on a protein that protects cancer and other cells from these stresses
could one day help doctors to break down cancer cells’ defenses, making them
more susceptible to treatment.
In The Journal of Biological Chemistry, scientists led by USC
professor Kelvin J. A. Davies demonstrated that a protein known as Nrf2 governs
a cell’s ability to cope with oxidative stress by increasing the expression of
key genes for removing damaged proteins.
Typically, oxidative stress is to be avoided. People eat foods high in
antioxidants, such as fruits and vegetables, to try to block oxidation in their
cells, in hopes of lowering their risk of illnesses, such as cancer, heart
disease, stroke, and Alzheimer’s disease—which all are linked to oxidative
stress.
But in the case of cancer cells, if the Nrf2 response some day could be
selectively turned off, treatments like chemotherapy and radiation could be
more effective, Davies said.
“One of the problems you have is that cancer cells start becoming resistant
to those treatments—they adapt,” said Davies, who holds appointments at the USC
Davis School of Gerontology the USC Dornsife College of Letters, Arts, and
Sciences. “The next time they may be more resistant because they’ve seen it
before.”
Nrf2 is a transcription factor protein, meaning that it binds to specific
sequences of DNA, turning on the process of copying the blueprints encoded in
those DNA sequences into functional enzymes.
In particular, the new work from the Davies laboratory shows that production
of proteasome and a proteasome regulator (Pa28) is controlled by Nrf2 during
oxidative stress. Proteosome, in turn, is a large protein enzyme that breaks
down oxidized proteins that otherwise would accumulate and cause cells to die.
When oxidative stress increases (which can be simulated in the lab by adding
hydrogen peroxide—the major product of both radiation therapy and chemotherapy),
Davies and his team found that the Nrf2 in a cell starts ramping up proteasome
production.
The researchers then tested their findings by blocking Nrf2 with various
chemical and genetic inhibitors, which decreased the cell’s ability to make
more proteasome and cope with the hydrogen peroxide.
In normal young cells, Nrf2 allows continuous regulation of proteasome
production in response to changing oxidative environments. This ability may
decline in aging and age-related diseases, making older individuals less able
to cope with stress.
“We would like to be able to reverse this decline in normal cells while
making cancer cells less stress-resistant and more easily killed by radiation
therapy and chemotherapy,” Davies said.
