Harvard: Considerable evidence has indicated that a drug used for more than 50 years to treat Type 2 diabetes can also prevent or slow the growth of certain cancers. But the mechanism behind metformin’s anticancer effects has been unknown. Now, a team of Harvard Medical School investigators at Massachusetts General Hospital has identified a pathway that appears to underlie metformin’s ability both to block the growth of human cancer cells and to extend the lifespan of the C. elegans roundworm. Their findings imply that this single genetic pathway plays an important role in a wide range of organisms.
“We found that metformin reduces the traffic of molecules into and
out of the nucleus—the ‘information center’ of the cell,” said Alexander Soukas, HMS assistant professor of medicine at Mass General and senior author of the study published in Cell.
“Reduced nuclear traffic translates into the ability of the drug to
block cancer growth and, remarkably, is also responsible for metformin’s
ability to extend lifespan,” Soukas said. “By shedding new light on
metformin’s health-promoting effects, these results offer new potential
ways that we can think about treating cancer and increasing healthy
Metformin appears to lower blood glucose in patients with Type 2
diabetes by reducing the liver’s ability to produce glucose for release
into the bloodstream. Evidence has supported the belief that metformin
blocks the activity of mitochondria, the powerhouses of the cell. But,
Soukas said, more recent information suggests the mechanism is more
Several studies have shown that individuals taking metformin have a
reduced risk of developing certain cancers and of dying from cancers
that do develop. Current clinical trials are testing the impact of
metformin on cancers of the breast, prostate and pancreas. Several
research groups are working to identify its molecular targets.
Soukas’ team had observed that, just as it blocks the growth of cancer cells, metformin slows growth in C. elegans, suggesting that the roundworm could serve as a model for investigating the drug’s effects on cancer.
Their experiments found that metformin’s action against cancer relies
on two elements of a single genetic pathway: the nuclear pore complex,
which allows the passage of molecules into and out of the nucleus, and
an enzyme called ACAD10. Basically, metformin’s suppression of
mitochondrial activity reduces cellular energy, restricting the traffic
of molecules through the nuclear pore. This shuts off an important
cellular growth molecule called mTORC1, resulting in activation of
ACAD10, which both slows the growth and extends the lifespan of C. elegans.
In human melanoma and pancreatic cancer cells, the investigators
confirmed that drugs in the metformin family induced ACAD10 expression,
an effect that depended on the function of the nuclear pore complex.
Without the complete signaling pathway—from mitochondrial suppression
through nuclear pore restriction to ACAD10 expression—cancer cells were
no longer sensitive to the effects of metformin-like drugs.
“Amazingly, this pathway operates identically, whether in the worm or
in human cancer cells,” said Soukas. “Our experiments showed two very
important things: If we force the nuclear pore to remain open or if we
permanently shut down ACAD10, metformin can no longer block the growth
of cancer cells. That suggests that the nuclear pore and ACAD10 may be
manipulated in specific circumstances to prevent or even treat certain
The essential contribution of ACAD10 to metformin’s anticancer action
is intriguing, Soukas added, because the only published study on ACAD10
function tied a variant in the gene to the increased risk of Type 2
diabetes in Pima Indians, suggesting that ACAD10 also has a role in the
drug’s antidiabetes action.
“What ACAD10 does is a great mystery that we are greatly interested
in solving,” he said. “Determining exactly how ACAD10 slows cell growth
will provide additional insights into novel therapeutic targets for
cancer and possibly ways to manipulate the pathway to promote healthy
Support for this study includes National Institutes of Health grants
R03DK098436, K08DK087941, R01DK072041 and R01CA166717; a Broad Institute
SPARC Grant; and the Ellison Medical Foundation New Scholar in Aging