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.
Highlights
Examination of clinical materials using several distinct and complementary techniques has the potential to yield new perspectives in physiology and pathophysiology which might not be evident using each technique in isolation
This work is unique from other metabolic studies in renal cell carcinoma (RCC) due to its concurrent utilization of two distinct complementary techniques to generate and validate reprogrammed energy metabolism and tryptophan pathways in RCC, thereby ameliorating some of the drawbacks and deficiencies of each omics technique as used in isolation
It has long been known that most solid tumors utilize aerobic glycolysis/lactic acid fermentation in order to provide sufficient energy for cell metabolism, as well as to synthesize key membrane components and other cellular building materials [4, 18,19,20]
Summary
Examination of clinical materials using several distinct and complementary techniques has the potential to yield new perspectives in physiology and pathophysiology which might not be evident using each technique in isolation. Due to the highly specialized nature of each omics technique and its associated analysis, each investigator tends to have a relatively narrow range of expertise directed towards but a single omics strategy; for this reason, it is rare to find a merging of several of these powerful techniques in a single study Such single omics studies can be problematic for interpretation, for example the quantity of proteins (e.g. enzymes) as the output of proteomics does not always correlate with their activities, and many gene transcripts undergo post-transcriptional processing. It is a logical extension in this field to combine data from several complementary omics techniques to attempt to eliminate some of the bias inherent in a single method, and it is critical to validate the proposed hypotheses which come out of the omics data both in vitro and in vivo [2, 3]
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