COLUMBUS, Ohio – New data show that ammonia – typically known as a waste byproduct from protein degradation that is excreted from the human body through urine – plays a key role in fueling the rapid growth of certain aggressive forms of cancer. Representing the culmination of more than a decade of laboratory research, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) team reports new findings showing that ammonia is not a waste molecule – it plays a critical role in activating fat production in cancer cells, promoting cancer growth and spread. Their findings appear in a recent issue of Nature Metabolism. “We know that tumor cells consume abundant sugar (glucose) and amino acids and convert them to fat for rapid growth, but it has been a mystery how tumor cells sense nutrient levels to turn on fat production machinery,” said Dr. Deliang Guo, who is the Urban and Shelly Meyer Professor of Cancer Research with the OSUCCC – James Translational Therapeutics Program and a professor at The Ohio State University College of Medicine. “Our work has uncovered a surprising turn on switch for these tumor cells: ammonia, which is produced as a waste byproduct in the cell metabolism process and acts as a key signaling molecule telling tumor cells making fat.” These new data detail how ammonia plays a critical role in activating lipid synthesis in cancer cells specifically, leading to tumor growth and spread. Study background and methods In the healthy human body, excess glucose (blood sugar) is stored as lipids in the form of fatty acids, cholesterol and other substances through a process called lipogenesis that is managed in the liver and fat cells. This process is activated and regulated by specific proteins in the body called SREBPs (sterol regulatory-element binding proteins). Many types of cancers can grow uncontrollably by activating this lipid production molecular pathway. “We knew from previous research that lipid production is stopped when too many sterols (lipids like cholesterol) build up in a cell. However, we did not know how cells ‘turned on’ lipid production in the first place. Our lab was established with the goal of understanding what molecular signaling flips that ‘on’ switch so that we can stop the process of lipogenesis that leads to metastatic cancer,” Guo said. “If we find it, we can turn it off to effectively suppress tumor growth and metastasis, and also treat various metabolic diseases”. Guo’s research lab spent more than a decade conducting research to understand how more aggressive forms of cancer – specifically glioblastoma (brain), breast, skin, lung, liver and pancreatic – can rapidly produce lipids. Their early research published in the journal Cancer Cell in 2015 found that glucose was necessary for lipid production, not just because glucose is converted to lipids, but also because it needs to be present for SREBPs to activate. However, glucose alone could not trigger lipogenesis. Through extensive, long-term research they found that ammonia from glutamine (a building block of protein) was also required. In fact, it was ammonia that actually activates the SREBPs that tell the cell to make lipids. The team’s newly published data details how tumor cells use glutamine to produce ammonia. Together with glucose, this activates lipid production and aggressive tumor growth. “This is a major breakthrough in our scientific understanding of how tumor cells simultaneously meet their abnormally high requirements for energy and cellular building materials by de-regulating lipid (fat and oil) synthesis, and it provides important insights to guide future targeted cancer therapies,” said Dr. Chunming Cheng, first author of the study and a research scientist with the OSUCCC – James. “These findings could truly revolutionize our understanding and treatment of many cancers and metabolic disorders.” Coauthors in this study include Feng Geng, Zoe Li, Yaogang Zhong, Huabao Wang, Xiang Cheng, Yue Zhao, Xiaokui Mo, Arnab Chakravarti and Xiaolin Cheng of The Ohio State University; Craig Horbinski of Northwestern University and Wenrui Duan of The Florida International University. This research was supported by grants from National Institute of Neurological Disorders and Stroke (NINDS) and National Cancer Institute (NCI) of United States grants R01NS104332, R01NS112935, R01CA227874 and R01CA240726 and American Cancer Society (United States) Research Scholar grant RSG-14-228-01–CSM. We also appreciate the support from OSUCCC-Pelotonia (United States) Idea grant and Urban and Shelly Meyer Foundation. To learn more about research underway through the OSUCCC – James and the Center for Cancer Metabolism, visit cancer.osu.edu. -30-