High-fat diet, unregulated athletic exercise endurance enhancers linked to pancreatic cancer risk

Researchers at University of Michigan Rogel Cancer Center found that a cellular nuclear receptor activated by high fat diets and synthetic substances in unregulated athletic performance enhancers fuels the progression of pancreatic precancerous lesions to pancreatic cancer.

Pancreatic ductal adenocarcinoma is a highly fatal form of cancer with increasing frequency, and strategies to prevent and treat the disease are urgently needed. Most cases of pancreatic cancer arise from precancerous lesions called pancreatic intraepithelial neoplasia; it is estimated that approximately 55-80% of adults over the age of 40 have these low-grade precancerous silent pancreatic lesions. A study published in Nature Communicationdirected by Imad Shureiqi, MDshows that precancerous pancreatic lesions in mice, similar to those found in humans, contain higher levels of the transcriptional peroxisome proliferator-activated receptor-delta (PPARδ).

PPARδ regulates the expression of a broad spectrum of key genes that influence biological processes such as lipid metabolism and cancer formation. Activation of PPARδ considerably accelerates the progression of precancerous lesions into pancreatic cancer. Shureiqi previously worked at the University of Texas MD Anderson Cancer Center where he conducted much of this study, particularly in partnership with Xiangsheng Zuo, MD, Ph.D., before transferring his research to the cancer center in 2020.

“We became interested in studying the effects of PPARδ on pancreatic carcinogenesis because our previous observations showed that PPARδ strongly promotes other gastrointestinal cancers. But there is very little information on the role of PPARδ in the development of pancreatic cancer,” Shureiqi said.

PPARδ activation is correlated with excessive exposure to certain ligands, both natural and synthetic. Certain ligands are naturally present in high-fat diets, which have been linked to an increased risk of pancreatic cancer in humans and animal models. High-fat diets are enriched with fatty acids which are natural PPARδ ligands.

Other synthetic forms of PPARδ ligands, such as cardarine (GW501516), are found in exercise supplements, aimed at improving physical performance and endurance. GW501516 was originally designed by pharmaceutical companies to encourage the body to use more fat and to treat non-cancerous conditions such as obesity and hyperlipemia. Pharmaceutical development of GW501516 and other similar potent PPARδ agonists for medical use has long been halted due to their potential pro-cancer side effects. Although studies of how PPARδ affects colorectal cancer date back to 1999 and pharmaceutical companies have halted development of synthetic PPARδ ligands, unregulated Internet outlets still sell substances like cardarine. The ads are largely aimed at young people, claiming it will help them build muscle endurance and burn fat.

Shureiqi explains that initially, researchers found that these synthetic ligands reduced fatigue in mice. This news made its way to mainstream media, which dubbed it “exercise in a pill.” “Unfortunately, what the media didn’t address was the dark side of PPARδ. Like muscle cells, synthetic PPARδ ligands also help cancer cells get more energy from fat as a fuel source,” he said.

“It’s shocking to me,” Shureiqi continued. “Animal models repeatedly show the strong relationship between PPARδ and cancer promotion in the case of colorectal cancer and stomach cancer. Now we get more information on how it affects pancreatic cancer.

The critical factors that promote progression from silent pancreatic precancerous lesions to pancreatic cancer remain poorly defined, especially those that are easy to target. Although most of these precancerous lesions do not turn into cancer, understanding how they evolve is still critical to finding interventions to combat the rising rate of pancreatic cancer. The results of this study indicate that people who have silent precancerous lesions, even low-grade ones, may increase their risk of developing pancreatic cancer by consuming natural PPARδ activators, such as in high-fat, or synthetic diets, like cardarine. Future development of agents effective in blocking PPARδ activation could provide a new approach to prevent the progression of precancerous lesions to pancreatic cancer. Limiting exposure to high-fat diets could also be considered for people with a high prevalence of precancerous pancreatic lesions. But for now, the most pressing concerns are the widespread sales and use of these synthetic, athletic-enhancing PPARδ-activating substances.

“This new information should alert individuals to the serious potential health risks associated with the use of synthetic PPARδ agonists,” Shureiqi said. “We are trying to get the message across that using these substances is not a good idea. It might improve muscle endurance, but it also improves the cancer’s ability to use energy and grow.

Funding: grants from the National Cancer Institute R01CA266223, R01CA142969, R01CA195686, R01-CA206539, R01CA236905 R03CA235106, K08CA234222; Texas Institute for Cancer Prevention and Research grants RP150195 RP140224;, DDC Seed Fund. This study used the MD Anderson Cancer Center Genetically Engineered Mouse Facility, Functional Genomics Core, Flow Cytometry and Cellular Imaging Facility, Next Generation Sequencing Core and Research Animal Support Facility-Smithville Laboratory Animal Genetic Services, supported by the Center Support Grant oncology P30CA016672 . The Next Generation Sequencing Core was also supported by CPRIT Core Facility Support Grant RP120348.

Article quoted: Rapid acceleration of KRAS mutant pancreatic carcinogenesis via tumor immune microenvironment remodeling by PPARδ”, Nature Communications. DOI: 10.1038/s41467-022-30392-7

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