Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis

TLDR

Kidney cancer, or renal cell carcinoma, is known as “the internist’s tumor” because its diverse systemic manifestations suggest it exploits complex, non‑physiologic metabolic pathways. The study aimed to determine how metabolic reprogramming in renal cell carcinoma enables escape from current therapies. The authors performed combined grade‑dependent proteomics and metabolomics analysis of human RCC tissue. Higher‑grade RCC exhibits a shift toward the Warburg effect with reduced TCA cycle activity, enhanced glutamine‑driven antioxidant glutathione production, suppressed β‑oxidation with elevated fatty acylcarnitines, and increased tryptophan catabolism linked to immune suppression, supporting the use of antimetabolic therapies.

Abstract

Kidney cancer [or renal cell carcinoma (RCC)] is known as "the internist's tumor" because it has protean systemic manifestations, suggesting that it utilizes complex, nonphysiologic metabolic pathways. Given the increasing incidence of this cancer and its lack of effective therapeutic targets, we undertook an extensive analysis of human RCC tissue employing combined grade-dependent proteomics and metabolomics analysis to determine how metabolic reprogramming occurring in this disease allows it to escape available therapeutic approaches. After validation experiments in RCC cell lines that were wild-type or mutant for the Von Hippel-Lindau tumor suppressor, in characterizing higher-grade tumors, we found that the Warburg effect is relatively more prominent at the expense of the tricarboxylic acid cycle and oxidative metabolism in general. Further, we found that the glutamine metabolism pathway acts to inhibit reactive oxygen species, as evidenced by an upregulated glutathione pathway, whereas the β-oxidation pathway is inhibited, leading to increased fatty acylcarnitines. In support of findings from previous urine metabolomics analyses, we also documented tryptophan catabolism associated with immune suppression, which was highly represented in RCC compared with other metabolic pathways. Together, our results offer a rationale to evaluate novel antimetabolic treatment strategies being developed in other disease settings as therapeutic strategies in RCC.