An NCI-designated Comprehensive Cancer Center
By Zen Vuong | November 1, 2019
John Termini DNA Damage | City of Hope Human kidney cells stained to reveal DNA damage induced by elevated glucose (green dots)
Higher-than-normal blood sugar levels are linked to more DNA damage that is repaired less often in the body’s cells, which could explain why people with diabetes have an increased risk of developing cancer, according to ongoing research led by City of Hope.
 
Such genomic instability can cause and promote the progression of cancer, said John Termini, Ph.D., professor in the Department of Molecular Medicine.
 
“As the incidence of diabetes continues to rise, the cancer rate will likely increase as well,” Termini said. “In an ironic twist of fate, some cancer treatments increase the risk of diabetes, which in turn increases the risk of cancer. The destructive machine feeds itself. That’s why City of Hope — best known for its leading-edge cancer therapies — has also taken on the challenge of finding a cure for diabetes.”

Similar risk factors

The diabetes and cancer link has been discussed in scientific circles for years; however, researchers are still searching for the disease-causing catalyst. This research may bring us one step closer to finding it. Termini presented his ongoing research at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition on Aug. 25 in San Diego. He elaborated on early findings at an ACS press conference on Aug. 26.
 
The link between diabetes and certain cancers may be due, in part, to shared risk factors such as aging, obesity, increased inflammation, dietary choices and inactive lifestyles. People with type 2 diabetes (the most common form) are 2.5 times more likely to develop liver or pancreatic cancer. They also run a higher-than-normal risk of developing colon, bladder and breast cancer. Diabetic women with breast cancer have a higher mortality rate than women with breast cancer alone.
 
Conversely, some forms of chemotherapy induce insulin resistance, bringing on diabetic symptoms. Immunotherapy, one of the most exciting advances in cancer treatment, may bring on the less common type 1 diabetes, which is essentially an autoimmune disorder. With immunotherapy, the body's immune system is “unleashed,” and it may attack critical insulin-producing cells in the pancreas.
 
Termini and his colleagues showed, in tissue culture and diabetic mouse models, that elevated glucose increased the presence of DNA adducts — chemical modifications of the DNA. Specifically, they found that a DNA adduct called N2-(1-carboxyethyl)-2’-deoxyguanosine, or CEdG, occurred more frequently in diabetic models than in normal cells or mice. Moreover, high glucose levels increased DNA strand breaks and interfered with DNA repair, which is required for removal of CEdG. The result is genome instability that could cause cancer.
 
Recently, Termini and colleagues completed a clinical study that measured the levels of CEdG and its RNA counterpart (CEG) in people with type 2 diabetes. People with diabetes had significantly higher levels of both CEdG and CEG than people without the disease.
 
The scientists identified two proteins that appear to be involved: transcription factor HIF1α and signaling protein mTORC1, both of which are less active in people with diabetes. HIF1α activates several genes involved in the repair process. The scientists found that if they stabilized HIF1α in a high-glucose environment, they increased DNA repair and reduced DNA damage. The protein mTORC1 controls HIF1α, so if mTORC1 is stimulated, then HIF1α is stimulated, Termini said.

Metformin May Reduce cancer risk

In theory, a medication that lowers blood sugar levels in diabetics could also potentially fight cancer by “starving” malignant cells to death. Evidence exists showing that diabetics who take metformin, the No. 1 drug for treating type 2 diabetes, may be less likely to develop cancer. Moreover, if they contract cancer, they are significantly less likely to die from it.
 
“Metformin helps lower blood glucose levels and stimulates DNA repair,” Termini said. “We’re looking to test metformin in combination with drugs that specifically stabilize HIF1α or enhance mTORC1 signaling in diabetic animal models.”
 
These studies were supported by the National Institutes of Health. The ACS is the world’s largest scientific society.
  
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