Public Release: 

Mass. General study reveals how diabetes drug metformin prevents, suppresses cancer growth

Ancient genetic pathway could provide targets for fighting cancers, supporting healthy aging

Massachusetts General Hospital

Considerable evidence has indicated that the drug metformin, used for more than 50 years to treat type 2 diabetes, also can prevent or slow the growth of certain cancers; but the mechanism behind its anticancer effects has been unknown. Now a team of Massachusetts General Hospital (MGH) investigators 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, implying 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," says Alexander Soukas, MD, PhD, of the MGH Center for Human Genetic Research, senior author of the study in the Dec. 15 issue of 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. 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 aging."

Metformin's ability to lower blood glucose in patients with type 2 diabetes appears to result from the drug's effects on the liver -- reducing the organ's ability to produce glucose for release into the bloodstream. Evidence has supported the belief that this is the result of metformin's ability to block the activity of mitochondria, structures that serve as the powerhouse of the cell. But while that explanation appears to be fairly straightforward, Soukas explains, more recent information suggests the mechanism is more complex.

Several studies have suggested 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; and several research groups are working to identify its molecular targets. Soukas's 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 application of 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," says Soukas, who is an assistant professor of Medicine at Harvard Medical School. "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 cancers."

The essential contribution of ACAD10 to metformin's anticancer action is intriguing, Soukas adds, 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 says. "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 aging."

###

Lianfeng Wu, PhD, of the MGH Center for Human Genetic Research (CHGR) is lead author of the Cell paper. Additional co-authors are Ben Zhou, PhD, Christopher Webster, PhD, Michael Kacergis, MS, and Michael Talkowski, PhD, MGH CHGR; Noriko Oshiro-Rapley, PhD, Fan Mou, PhD, and Christopher Carr, PhD, MGH Department of Molecular Biology; Man Li, PhD and Bin Zheng, PhD, MGH Cutaneous Biology Research Center; and Joao Paulo, PhD and Steven Gygi, PhD, Harvard Medical School. Support for this study includes NIH grants R03DK098436, K08DK087941, R01DK072041, and R01CA166717, a Broad Institute SPARC Grant, and the Ellison Medical Foundation New Scholar in Aging Award.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.