Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis

Abstract

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

Glutathione Metabolism in Renal Cell Carcinoma Progression and Implications for Therapies

“…Proteome profiles of pRCC versus matching healthy tissues have indicated a tremendous reprogramming of main metabolic pathways. Oxidative phosphorylation, the TCA cycle, branched-chain amino acids, cytochrome P450 drug metabolism, peroxisomes, fatty acid metabolism, and several amino acid metabolism pathways were significantly decreased in pRCC, whereas the spliceosome, the ribosome, and the cell cycle were significantly increased [46]. A striking anticorrelation between the proteome and the transcriptome data [18] was identified for oxidative phosphorylation.…”

“…Furthermore, the discrepancy between the transcripts and proteins of the respiratory chain in RCC can also originate from the regulation of post-translational modifications. The metabolome indicated a tremendous increase of reduced and oxidized GSH levels in pRCC tissues [46], as well as significantly increased rates of GSH de novo synthesis based on glutamine consumption in the pRCC-derived cell lines Caki-2 and ACHN [46]. All of these alterations can in principle serve as potential therapeutic targets.…”

“…A cystine addiction of VHL-deficient RCC cells was identified, and the deprivation thereof or treatment with erastin or sulfasalazine in RCC cells induced cell death [100]. Chromophobe RCC, but not pRCC, was found to have significantly increased abundances of the VDAC1, VDAC2, and VDAC3 proteins [46,57] and should have a good response to treatment with erastin. Sulfasalazine has been in use for over 50 years for the treatment of inflammatory conditions such as arthritis.…”

“…MacKinnon et al [103] found that the abundance of pyruvate carboxylase (PC), which catalyzes the conversion of pyruvate to oxaloacetate to fuel the TCA cycle, strongly correlated with resistance, and knockdown of PC reduced TCA cycle activity and sensitized cells to CB-839 treatment, suggesting that PC expression may be a biomarker of resistance to CB-839. Chromophobe RCC and pRCC have been reported recently to have low PC expression [46,57]: They may lack this mechanism and therefore would probably be sensitive to CB-839. In addition, decreases in mTOR signaling were also observed in RCC cell lines that were sensitive to CB-839, indicating that CB-839-induced glutamate deprivation has a direct influence on the mTOR pathway [102].…”