There is increasing evidence for the role of altered metabolism in the pathogenesis of renal cancer.
Objective
This review characterizes the metabolic effects of genes and signaling pathways commonly implicated in renal cancer.
Evidence acquisition
A systematic review of the literature was performed using PubMed. The search strategy included the following terms: renal cancer, metabolism, HIF, VHL.
Evidence synthesis
Significant progress has been made in the understanding of the metabolic derangements present in renal cancer. These findings have been derived through translational, in vitro, and in vivo studies. To date, the most well-characterized metabolic features of renal cancer are linked to von Hippel-Lindau (VHL) loss. VHL loss and the ensuing increase in the expression of hypoxia-inducible factor affect several metabolic pathways, including glycolysis and oxidative phosphorylation. Collectively, these changes promote a glycolytic metabolic phenotype in renal cancer. In addition, other histologic subtypes of renal cancer are also notable for metabolic derangements that are directly related to the causative genes.
Conclusions
Current knowledge of the genetics of renal cancer has led to significant understanding of the metabolism of this malignancy. Further studies of the metabolic basis of renal cell carcinoma should provide the foundation for the development of new treatment approaches and development of novel biomarkers.
Introduction
Renal cell carcinoma (RCC) is among the top 10 most common malignancies in both men and women. In 2012, it is estimated that approximately 64 000 individuals will be diagnosed, with an estimated 13 570 dying from this disease in the United States [1]. Although the incidence has been increasing in the United States, the rates have leveled off or even declined in other parts of the world [2].
It is now clear that altered metabolism plays a key role in the pathogenesis of many disease states. Moreover, there has been increasing recognition of the role of metabolism in the pathogenesis of cancer, including RCC. To date, most studies have examined the risk of RCC in disease with known metabolic links. For example, the rising incidence of RCC has paralleled the increase in body mass index, particularly in Western countries [3]. This finding has been validated by several recent studies that reported increased incidence of RCC in disease states with known effects on metabolism, including obesity and diabetes [4]. Additionally, links between atherosclerosis and the risk of RCC have been identified [5].
Collectively, these data point to the emerging link between metabolism and cancer. Correspondingly, treatment of these disease processes, such as statins for atherosclerosis, may be associated with a reduced risk of RCC [6]. With continued examination of this link, identification of metabolic factors may point to new directions for therapeutics as well as biomarkers for diagnosis and prognosis. This review will focus on the metabolic alterations in the more common variants of RCC and the clinical relevance of these alterations.
Section snippets
Evidence acquisition
We performed a systematic search of PubMed through May 2012. Search terms included renal cancer, metabolism, HIF, and VHL. Searches were limited to articles written in English. All authors screened the potential references retrieved by the search and a final consensus on all publications included in the present review was reached.
Evidence synthesis
Evidence related to the review and that examined general aspects of cancer metabolism was acquired. Next, metabolic aspects of RCC were analyzed based on the histologic subtype. Metabolic aspects of RCC are described in the context of genes commonly alerted for each subtype.
Conclusions
The last few decades have witnessed a marked advance in our understanding of the genetics of renal cancer, particularly ccRCC. ccRCC is remarkable for the fact that common genetic changes (ie, VHL loss) have dramatic effects on the metabolism that are biologically relevant to the growth and survival of renal tumor cells. As such, further studies into ccRCC will provide a unique opportunity for researchers to apply understanding of tumor metabolism to clinically relevant applications. These
Pyruvate dehydrogenase kinase 1 (PDK1) phosphorylates the pyruvate dehydrogenase complex, which inhibits its activity. Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis, which plays an important role in tumor progression. This study aims to elucidate how PDK1 promotes breast cancer progression. We found that PDK1 was highly expressed in breast cancer tissues, and PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α (hypoxia-inducible factor 1α) pathway. Further investigation showed that PDK1 promoted the protein stability of HIF-1α by reducing the level of ubiquitination of HIF-1α. The HIF-1α protein levels were dependent on PDK1 kinase activity. Furthermore, HIF-1α phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells. The phosphorylation of HIF-1α at Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1α with von Hippel-Lindau and prolyl hydroxylase domain. We also found that PDK1 enhanced HIF-1α transcriptional activity. In summary, PDK1 enhances HIF-1α protein stability by phosphorylating HIF-1α at Ser451 and promotes HIF-1α transcriptional activity by enhancing the binding of HIF-1α to P300. PDK1 and HIF-1α form a positive feedback loop to promote breast cancer progression.
We aimed to investigate the expression and prognostic role of NAA10 in clear cell renal cell carcinoma (ccRCC).
We performed a gene expression and survival analysis based on the human cancer genome atlas database of ccRCC patients (TCGA-KIRC).
The patients in the TCGA-KIRC (n = 537) were divided into two subgroups: NAA10-low and NAA10-high expression groups. NAA10-high ccRCC exhibited higher T stages (p = 0.002), a higher frequency of distant metastasis (p = 0.018), more advanced AJCC stages (p < 0.001), a lower overall survival time (p = 0.036), and a lower survival rate (p < 0.001). NAA10-high ccRCC was associated with increased activity of non-specific oncogenic pathways, including oxidative phosphorylation (p < 0.001) and cell cycle progression [G2 to M phase transition (p = 0.045) and E2F targets (p < 0.001)]. Additionally, the NAA10-high tumors showed reduced apoptosis via TRIAL pathways (p < 0.001) and increased levels of activity that promoted epithelial-mesenchymal transition (p = 0.026) or undifferentiation (p = 0.01). In ccRCC, NAA10 expression was found to be a negative prognostic factor in both non-metastatic (p < 0.001) and metastatic tumors (p = 0.032).
In ccRCC, NAA10 expression was shown to be a negative prognostic factor related to tumor progression rather than tumor initiation, and high NAA10 expression promoted epithelial-mesenchymal transition and undifferentiation.
The ccRCC spectrum is dominated by the carbon 2-3 doublet at the lactate C3 resonance (Figure 2B), as expected for glycolytic tissue. The prominence of lactate signal in the ccRCC spectrum is consistent with previously published reports of high lactate levels in ccRCC tumors (Hakimi et al., 2013; Sudarshan et al., 2013). The prominent 2-3 doublet in alanine C3 is also consistent with anaerobic glucose metabolism, when pyruvate is converted to alanine through a transamination reaction catalyzed by alanine aminotransferase (ALT) (Figure 2B).
Clear cell renal cell carcinoma (ccRCC) is the most common form of human kidney cancer. Histological and molecular analyses suggest that ccRCCs have significantly altered metabolism. Recent human studies of lung cancer and intracranial malignancies demonstrated an unexpected preservation of carbohydrate oxidation in the tricarboxylic acid (TCA) cycle. To test the capacity of ccRCC to oxidize substrates in the TCA cycle, we infused 13C-labeled fuels in ccRCC patients and compared labeling patterns in tumors and adjacent kidney. After infusion with [U-13C]glucose, ccRCCs displayed enhanced glycolytic intermediate labeling, suppressed pyruvate dehydrogenase flow, and reduced TCA cycle labeling, consistent with the Warburg effect. Comparing 13C labeling among ccRCC, brain, and lung tumors revealed striking differences. Primary ccRCC tumors demonstrated the highest enrichment in glycolytic intermediates and lowest enrichment in TCA cycle intermediates. Among human tumors analyzed by intraoperative 13C infusions, ccRCC is the first to demonstrate a convincing shift toward glycolytic metabolism.
