Hyperglycemia may induce DNA damage and inhibit DNA repair, which may explain why individuals with diabetes may have an increased risk for developing cancer, according to a researcher from City of Hope, Duarte, California, who presented these findings at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition.¹

“A number of meta-analyses have found that diabetes increases the risk of certain cancers, especially liver, pancreatic, endometrial, breast, and colon. The reasons for this have been elusive,” said John Termini, PhD, Professor in the Department of Molecular Medicine at City of Hope, an institution with a strong focus on both diabetes and cancer. “Now that cardiovascular treatment has improved so much, individuals with diabetes are living longer, and we are now seeing an increase in cancer in that population,” he added. “The question has been why. The most common assumptions have to do with endocrinologic mechanisms.”

Certainly, there are endocrinologic processes that could predispose a person to cancer; for example, adipokines, cytokines, and other inflammatory factors seem to be higher in individuals with obesity, he acknowledged, but although there is some evidence of this, “it’s not the whole story.”

Dr. Termini’s lab has been interested in DNA damage and what causes it. To this end, they are examining the relationship between diabetes and pathology associated with DNA damage, since, as he pointed out, “cancer is a disease of genomic instability.”

Role of DNA Adducts

Dr. Termini and his colleagues have shown, in tissue culture and in mouse models of diabetes, that elevated glucose increases the presence of DNA adducts—chemical modifications of DNA that can be induced endogenously, for example, as a result of glucose metabolism.

Basically, this adduct is a modified DNA base that can do a number of things: facilitate miscoding at the DNA or RNA level during replication or translation, induce DNA-strand breaks, interfere with protein binding, and disrupt chromatin architecture—all of which can interfere with the normal flow of information necessary to maintain cellular and genomic integrity. “We’ve been working on sorting out how these adducts impact biology in a number of different ways,” stated Dr. Termini.

Specifically, the adduct of interest is a guanosine derivative produced by the breakdown of glucose: N2-(1-carboxyethyl)-2´-deoxyguanosine (CEdG). High glucose levels increase DNA-strand breaks and also interfere with DNA repair, which is required for removal of CEdG. The result is genomic instability, which could precipitate cancer, Dr. Termini explained.

Dr. Termini’s lab has found that CEdG and its RNA analog CEG occur at significantly higher levels in mouse models of diabetes relative to normal mice, an effect also seen in cell-culture models. The researchers are also beginning to make that discovery in humans as well. In a recent study of 85 persons with diabetes, they saw higher levels of the CEdG adduct and its analog CEG than in persons with normal blood glucose levels.

On the Protein Level

Dr. Termini and colleagues have identified two proteins that appear to be involved in this process: the transcription factor HIF1α and the mTOR kinase, a catalytic subunit of the mTORC1 and mTORC2 complexes of the mTOR signaling pathway. These proteins demonstrate reduced expression as a result of chronic elevated glucose, and this could have clinical effects in people with diabetes.

“HIF1α is destabilized in diabetes and is known to be important in the pathology of diabetes. For example, its low expression is responsible for impaired wound healing, pancreatic dysfunction, and other associated complications,” explained Dr. Termini. HIF1α also activates several genes involved in the DNA-repair process; therefore, DNA repair is attenuated in diabetes, and this has negative genomic consequences.

When HIF1α is artificially stabilized in a high-glucose environment, DNA repair is enhanced, and DNA damage is lessened. The mTORC1 protein controls HIF1α protein synthesis; so, if mTORC1 is stimulated, then HIF1α is stimulated, he continued.

Oncologists are well familiar with the mTOR signaling pathway. “In the case of cancer, the mTOR pathway is stimulated, and we use mTOR inhibitors to attenuate it. In patients without diabetes, to stimulate that pathway would probably be a mistake. But in the context of diabetes, it’s stimulated initially by glucose; but over time—with chronic hyperglycemia, chronic hyperinsulinemia—protein synthesis declines.”

“That’s thought to be due to attenuation of protein synthesis in the mTOR pathway,” Dr. Termini said. “We think stimulating protein synthesis and mTORC1 will improve DNA repair and lessen genomic damage and cancer risk.”

Regarding treatment that is relevant to HIF1α, there are inhibitors of the hydroxylases (enzymes) that oxidize HIF1α and target it for proteasomal degradation or prevent it from binding to the transcription start site. At the ACS meeting, Dr. Termini and colleagues reported that high glucose levels increase the expression of the genes for these enzymes as well as the substrates required for oxidizing HIF1α. “We think the metabolic effect of high glucose is stimulating the degradation of HIF1α via these enzymes,” he added.

Ongoing and Future Clinical Research

It is known that DNA-related oxidative damage is elevated in diabetes, but glucose-associated adducts are elevated as well. Researchers are examining approximately 2,600 urine samples from the Diabetes Complications and Control Trial to see whether these DNA adducts increase prior to the onset of kidney disease.

In theory, a drug that lowers glucose levels could also potentially fight cancer by “starving” malignant cells to death. To this end, Dr. Termini and other research groups are evaluating the protective effect of metformin. “Recent reviews of available data² are reporting reductions (30%–50%) in the incidence of cancer among patients with diabetes taking metformin,” Dr. Termini said.

“Metformin is a simple, inexpensive compound. We don’t fully understand how it works, but it does stimulate DNA repair and can stabilize HIF1α and overcome its inhibition by glucose,” noted Dr. Termini. “We’re looking to test metformin in combination with drugs that specifically stabilize HIF1α or enhance mTORC1 signaling in animal models of diabetes. We’re pulling the dots together to find a pattern.” ■

DISCLOSURE: Dr. Termini reported no conflicts of interest.

REFERENCES

1. Termini J: American Chemical Society Fall 2019 National Meeting & Exposition. Abstract TOXI-4. Presented August 25, 2019.

2. Kasznicki J, Sliwinska A, Drzewoski J: Metformin in cancer prevention and therapy. Ann Transl Med 2:57, 2014.