Summary: A major mitochondrial pathway that
imbues cancer cells with the ability to survive in low-glucose environments has
been pinpointed by researchers. By identifying cancer cells with defects in
this pathway or with impaired glucose utilization, the scientists can predict
which tumors will be sensitive to these anti-diabetic drugs known to inhibit
this pathway.
For several years, a
class of anti-diabetic drugs known as biguanides, has been associated with
anti-cancer properties. A number of retrospective studies have shown that the
widely used diabetes drug metformin can benefit some cancer patients. Despite
this intriguing correlation, it has been unclear how metformin might exert its
anti-cancer effects and, perhaps more importantly, in which patients.
Now, Whitehead Institute scientists are beginning to unravel
this mystery, identifying a major mitochondrial pathway that imbues cancer
cells with the ability to survive in low-glucose environments. By finding
cancer cells with defects in this pathway or with impaired glucose utilization,
the scientists can predict which tumor will be sensitive to the anti-diabetic
drugs known to inhibit the pathway in question. Their work is described online
this week in the journal Nature.
To study how cancer cells survive in the kind of low-glucose
environment found within cancerous tumors, Kıvanç Birsoy and Richard Possemato,
postdoctoral researchers in Whitehead Member David Sabatini’s lab, developed a
system that circulates low-nutrient media continuously around cells. Of the 30
cancer cell lines tested within this system, most appeared unaffected by a lack
of glucose. However, a few of the lines thrived and reproduced rapidly, while
others struggled. The varied responses to a glucose shortage were puzzling.
“No one really understood why cancer cells had these responses
or whether they were important for the formation of the tumor,” says Possemato,
who coauthored the Nature paper with Birsoy. “The cancer-relevance of the
alterations that we found as underlying this response to low glucose will still
need to be investigated.”
Birsoy and Possemato wondered whether certain cancer cells’
susceptibility to a low glucose environment could be exploited to attack
tumors. They screened overly distressed cells for genes whose suppression
improved or further hindered the cells’ survival rates. The screen flagged
genes involved in glucose transportation and oxidative phosphorylation, a
metabolic pathway in mitochondria. The powerhouses of a cell, mitochondria are
membrane-bound organelles with their own DNA, including genes that control
oxidative phosphorylation.
Birsoy and Possemato hypothesized that cancer cells with
mutations in these genes are over-taxing their mitochondria under normal
conditions. When placed in a harsh, low-glucose environment, the mitochondria
are maxed out, and the cells suffer. If true, the hypothesis would suggest that
further impairing mitochondrial function, with biguanides—which are known
oxidative phosphorylation inhibitors—could push the mitochondria beyond their
limits, to the detriment of the cancer cells.
They first tested their hypothesis in vitro on 13 cell lines
with glucose utilization defects and mitochondrial DNA mutations. Compared to
control cells, those sensitive to low glucose were five to 20 times more
susceptible to phenformin, a more potent biguanide than metformin. Birsoy and
Possemato then tested phenformin’s effectiveness in mice implanted with tumors
derived from low-glucose-sensitive cancer cells. The drug inhibited the tumors’
growth.
“These results show that mitochondrial DNA mutations and glucose
import defects can be used as biomarkers for biguanide sensitivity to determine
if a cancer patient might benefit from these drugs,” says Birsoy. “And this is
the first time that anyone has shown that the direct cytotoxic effects of this
class of drugs, including metformin and phenformin, on cancer cells are
mediated through their effect on mitochondria.” To confirm the accuracy of
their proposed biomarkers, Birsoy and Possemato want to analyze previous
clinical trials to see if cancer patients with the proposed biomarkers fared
better with metformin treatment than patients without the biomarkers.
Posted by:
Gauri Shah
Faculty (BII)
