Glucose metabolism and cancer

The first identified biochemical hallmark of tumor cells was a shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis. We now know that much of this metabolic conversion is controlled by specific transcriptional programs. Recent studies suggest that activation of the hypoxia-inducible factor (HIF) is a common consequence of a wide variety of mutations underlying human cancer. HIF stimulates expression of glycolytic enzymes and decreases reliance on mitochondrial oxidative phosphorylation in tumor cells, which occurs even under aerobic conditions. In addition, recent efforts have also connected the master metabolic regulator AMP-activated protein kinase (AMPK) to several human tumor suppressors. Several promising therapeutic strategies based on modulation of AMPK, HIF and other metabolic targets have been proposed to exploit the addiction of tumor cells to increased glucose uptake and glycolysis.

Introduction

Well over a century ago, Pasteur first noted the inverse relationship between two modes of glucose metabolism, finding that the absence of oxygen resulted in the inhibition of oxidative phosphorylation (OXPHOS) and a switch to glycolysis for ATP generation (the ‘Pasteur effect’). In the 1920s, Otto Warburg made the surprising finding that tumor cells, unlike their normal counterparts, utilize glycolysis instead of mitochondrial oxidative phosphorylation for glucose metabolism even when in oxygen-rich conditions (the ‘Warburg effect’) [1]. Warburg further proposed that defects in energy metabolism, specifically in mitochondria, may be at the root of cancer (the ‘Warburg hypothesis’). Otto Warburg was awarded the Nobel Prize in 1931 for his breakthrough work on mitochondrial respiration, although his hypothesis on the basis of cancer was slowly discredited [2]. As discoveries of the genetic basis for cancer bloomed in the 1980s, changes in tumor metabolism became viewed as secondary events, perhaps simply due to the lack of oxygen in hypoxic tumor conditions. The discovery of the hypoxia-inducible HIF-1 transcription factor and the finding that it directly controls the transcription of nearly every enzyme of glycolysis provided a potential molecular mechanism for the effects of hypoxia on the glucose metabolism of tumors. Moreover, in recent years several studies have discovered that several oncogenic and tumor suppressor mutations found in a wide variety of human cancers can directly activate HIF-1 and other components of glucose metabolism independently of hypoxia. The accumulating data suggest that the altered metabolism of tumor cells is in fact genetically controlled by the very mutations that give rise to cancer.

Coincident with these basic research discoveries, the increasing clinical use of [¹⁸F] flouro-2-deoxyglucose (FDG) positron emission tomography (PET) in the visualization of a wide variety of human tumor types revealed that glucose metabolism is functionally altered in a wide variety of human cancer types. FDG injected into the bloodstream is taken up by glucose transporters on the cell surface and then phosphorylated by hexokinase to form FDG-phosphate, thereby enabling visualization of the tissues with the greatest glucose uptake and hexokinase activity [3]. In addition, cell culture studies demonstrated that tumor cells bearing these metabolic changes are uniquely sensitive to inhibition of glycolysis — unlike their normal counterparts — suggesting a potential therapeutic window. Here I focus on recent breakthroughs in our understanding of how metabolism is tied to growth control, and how its disruption contributes to tumorigenesis.