Papillary renal cell carcinomas rewire glutathione metabolism

Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7-20% of all renal cell tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls and transcriptome data derived from TCGA were used to elucidate the regulation of metabolic pathways and underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was tremendously increased in pRCC type I, II, and metastatic type II and can be regarded as a new hallmark in this malignancy. Isotope tracing revealed an increased de novo synthesis rate of GSH and a glutamine addiction in pRCC derived cell lines. Furthermore, a rewiring of the main pathways involved in ATP and glucose synthesis was observed on the protein level: the abundance of enzymes involved in gluconeogenesis and of the respiratory chain was found to be significantly reduced in pRCC. In contrast, transcripts encoding for the respiratory chain were not regulated, which prompts for non-genetic profiling. The main molecular characteristics of pRCC are the increased GSH synthesis to cope with ROS stress, the deficient anabolic glucose synthesis, and the compromised oxidative phosphorylation, which could be exploited in novel anti-cancer strategies.