(Ivanhoe Newswire) -- Cell cycle checkpoints act like molecular tripwires
for damaged cells. Leave the tripwire in place for too long, however, and cancer
cells will press on regardless, making them resistant to certain types of
chemotherapy, according to researchers at the Salk Institute for Biological
Studies.
"A lot of progress has been made in understanding the molecular details of
checkpoint activation," senior author Tony Hunter, Ph.D., a professor in the
Molecular and Cell Biology Laboratory was quoted as saying, "but checkpoint
termination, which is essential for the resumption of cell cycle progression, is
less well understood."
"If we could screen tumors for markers of chemo-resistance, we could then adjust
the treatment accordingly," first author You-Wei Zhang, Ph.D., formerly a
postdoctoral researcher in Hunter's lab and now an assistant professor at Case
Western Reserve University in Cleveland, Ohio, was quoted as saying.
In response to DNA damage and blocked replication, eukaryotes activate the DNA
damage checkpoint pathway, which stops the cell cycle, buying the cell time to
repair damage and recover from stalled or collapsed replication forks. If not
repaired, these errors can either kill a cell when it attempts to divide or lead
to genomic instability and eventually to cancer.
A key role in this process is played by the checkpoint protein Chk1, which
responds to stressful conditions induced by hypoxia, DNA damage–inducing cancer
drugs, and irradiation. These same conditions set the protein up for eventual
degradation. But how the cellular protein degradation machinery knows that it is
time to dispose of activated Chk1 was unclear.
In
his experiments, Zhang discovered that activation of Chk1 exposes a specific
string of amino acids that attracts the attention of a protein known as Fbx6,
short for F box protein 6. Fbx6 in turn brings in an enzyme complex that flags
Chk1 proteins for degradation, allowing the cell to get rid of the activated
checkpoint protein. Once Chk1 is eliminated, cells will resume the cell cycle
progression, or, in the prolonged presence of replication stress, undergo
programmed cell death. Yet some cancer cells keep dividing even in the presence
of irreparable damage.
"Camptothecins are FDA-approved cancer drugs that induce replication stress and
stop cancer cells dividing, but their clinical antitumor activity is very
limited [because of] the relatively rapid emergence of drug resistance, and the
mechanisms are poorly understood," said Hunter. "We wondered whether defects in
the Chk1 destruction machinery might allow cells to ignore the effects of
camptothecin and similar drugs used for chemotherapy."
When Zhang checked cultured cancer cell lines and breast cancer tissue, he found
that low levels of Fbx6 predicted high levels of Chk1 and vice versa. But most
importantly, he was able to demonstrate that two of the three most camptothecin-resistant
cancer cell lines displayed significant defects in camptothecin-induced Chk1
degradation, which seemed to be caused by very low levels of Fbx6 expression.
"Chk1 and Fbx6 clearly play an important role for the regulation of the response
to chemotherapy," he says. "One day, they could become an important prognostic
marker that predicts patients' responsiveness to drugs such as irinotecan,
platinum compounds, and gemcitabine, while Chk1 inhibitors might increase tumor
cells' sensitivity to these drugs." Such a combination therapy could overcome
clinical resistance or allow doctors to reduce the amount of administered drug,
thereby reducing the often debilitating side effects.
SOURCE: Molecular Cell, August 28, 2009
