Aerobic glycolysis: a novel target in kidney cancer

Abstract

Renal cell carcinoma (RCC) is a heterogenous group of cancers that arise from the nephron. While there are distinct histologic subtypes associated with common genetic alterations, most forms of RCC are linked by a common pathway of dysregulated metabolism. Reliance on aerobic glycolysis, a feature of cancer first hypothesized by Warburg, is a common feature in sporadic and hereditary forms of kidney cancer. Two hereditary forms of RCC, succinate dehydrogenase (SDH) and hereditary leiomyomatosis and RCC (HLRCC), are characterized by mutations in Krebs cycle enzymes, rendering them dependent on glycolysis for energy requirements. The reliance on these pathways may make them vulnerable to novel metabolic strategies, including inhibition of glycolysis, glucose uptake and macromolecule biosynthesis.

Figure 1

Proposed mechanisms of tumorigenesis in HLRCC. Due to loss of function of fumarate hydratase, fumarate accumulates, inhibiting HIF prolyl hydroxylases (HPHs). Inactivation of HPH leads to intracellular HIF accumulation and transcription of important mediators of angiogenesis, growth and proliferation. In addition, upregulation of fumarate can lead to post-translational modification (succination of cysteine residues) and inactivation of KEAP1. This results in NRF2 dysregulation and transcriptional activation of several NRF2-dependant genes that mediate the cellular anti-oxidant response, Both HIF and NRF2 contribute to the aberrant metabolic signature associated with FH inactivation.

Figure 2

Macromolecule generation using glutamine as a biologic precursor.

Figure 3

Metabolic flow of glucose and opportunities for therapeutic intervention in cancer