Defining the Role of Renal Gluconeogenesis in Renal Cell Carcinoma

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Project Summary Renal cell carcinoma is the most common primary kidney cancer, representing 90-95% of primary renal neoplasms. Obesity and diabetes are associated with an increased risk of renal cell carcinoma, but the mechanisms by which systemic metabolic changes promote tumor progression are unknown. Although its reputation as a glucose-producing organ has been dwarfed by that of the liver over the years, the kidney possesses the same complement of gluconeogenic enzymes as the liver – with a higher concentration of gluconeogenic proteins per gram of tissue in the kidney, suggesting that its gluconeogenic capacity may even exceed the liver's. Glucose is well-known to be a crucial substrate for tumor growth; given the gluconeogenic activity of the kidney, it is likely that increased renal gluconeogenesis may fuel tumor growth. However, this phenomenon, and its mechanistic explanation, remains to be explored. We have recently found that fibroblast growth factor-21 (FGF-21) promotes renal gluconeogenesis during starvation by activating intrarenal lipolysis through a 2-adrenergic pathway, thereby activating pyruvate carboxylase flux in healthy rodents. Therefore, this proposal will test the Overarching Hypothesis that in renal cell carcinoma, increased FGF-21 acts through a similar mechanism to promote intrarenal lipolysis, pyruvate carboxylase activity, and as a result, gluconeogenesis, and that this increased renal glucose supply fuels tumor growth. We will also examine the utility of an FGF-21 neutralizing antibody against mice genetically prone to renal cell carcinoma, which we anticipate will reduce renal gluconeogenesis and renal cell carcinoma progression. If the hypotheses are confirmed, these data would identify FGF-21 – which is already being targeted in advanced clinical trials for metabolism- and diabetes-related indications – as a potential therapeutic target in renal cell carcinoma.