Cancer Research Articles

Tumor cells exhibit an altered metabolism, characterized by increased glucose uptake and elevated glycolysis, which was first recognized by Otto Warburg 70 years ago. Warburg originally hypothesized that these metabolic changes reflected damage to mitochondrial oxidative phosphorylation. Although hypoxia and hypoxia inducible factor can induce transcriptional changes that stimulate glucose transport and glycolysis, it is clear that these changes can occur in cultured tumor or transformed cells cultured under normoxic conditions, and thus there must be genetic alterations independent of hypoxia that can stimulate aerobic glycolysis. In recent years it has become clear that loss of p53 and activation of Akt can induce all or part of the metabolic changes reflected in the Warburg effect. Likewise, changes in expression of lactate dehydrogenase and other glycolytic control enzymes can contribute to increased or altered glycolysis. It is also clear that changes in lipid biosynthesis occur in tumor cells to support increased membrane biosynthesis and perhaps the altered energy needs of the cells. Changes in fatty acid synthase, Spot 14, Akt, and DecR1 (2,4-dienoylcoenzyme A reductase) may underlie altered lipid metabolism in tumor cells and contribute to the ability of tumor cells to proliferate or metastasize. Although these advances provide new therapeutic targets that merit exploration, there remain critical questions to be explored at the mechanistic level; this work may yield insights into tumor cell biology and identify additional therapeutic targets.

Introduction

For more than 70 years it has been appreciated that cancer cells exhibit an altered metabolism that is characterized by elevated uptake of glucose and an increased glycolytic rate; this observation was first reported by Otto Warburg [1], comparing liver cancer cells with normal liver cells. The observation that cancer cells generated the majority of their ATP by glycolysis, even when grown in the presence of oxygen, caused Warburg to hypothesize that the metabolic shift toward glycolysis observed in cancer cells reflected damage to mitochondrial respiration, which resulted in aerobic glycolysis. In normal cells the presence of oxygen inhibits glycolysis, as first recognized by Pasteur (the Pasteur effect) [2]. Furthermore, Warburg hypothesized that this metabolic change was the origin of cancer, as reflected in the title of his report published in 1956 [3]. It is now clear that the majority of tumor cells in vivo, and transformed cells in vitro, exhibit elevated levels of glucose transport and elevated rates of glycolysis that result in an increase in the production of lactate; this phenomenon is known as the Warburg effect.

Glycolysis is a topic covered in virtually every biochemistry course because of its central role in biology and is summarized in Figure 1. During glycolysis, glucose is metabolized to form two molecules of pyruvate with a net gain of two molecules of ATP from one molecule of glucose. Under normal conditions, pyruvate is converted into acetylcoenzyme A to provide starting material for the citric acid cycle and oxidative phosphorylation, which yields about 34 more molecules of ATP from the molecule of glucose. Despite inefficient use of glucose, tumor cells often convert pyruvate to lactate, which is secreted from the cell, but this change in metabolism is prominent and would appear to result from rather strong selective pressure. Tumor hypoxia (lack of oxygen) will also cause a shift to glycolytic metabolism, because respiration cannot occur without oxygen. Tumor hypoxia and activation of hypoxia inducible factor (HIF) is undoubtedly an important pathway that contributes to tumorigenesis, angiogenesis, increased glycolysis and tumor cell survival. Additionally, HIF can be activated under normoxia by loss of the von Hippel-Lindau tumor suppressor (which normally acts to keep levels of HIF activity low under normoxic conditions) or activation of receptor tyrosine kinase signaling [4]. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in von Hippel-Lindau deficient renal cell carcinoma by repression of c-Myc activity [4]. HIF activation not only stimulates glycolysis but also actively attenuates mitochondrial respiration, making HIF a key regulator of cancer cell