**Glucose Metabolism and Cancer**

Lei Zheng1,2, Jiangtao Li2 and Yan Luo3

*1The Sidney Kimmel Comprehensive Cancer Center, The Skip Viragh Center for Pancreatic Cancer, The Sol Goldman Pancreatic Cancer Center Department of Oncology, and Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 2Department of Surgery, The Second Affiliated Hospital Zhejiang University College of Medicine, Hangzhou 3Section of Biochemistry and Genetics, School of Basic Medical Sciences and Cancer Institute, the Second Affiliated Hospital Zhejiang University College of Medicine, Hangzhou 1USA 2,3China* 

### **1. Introduction**

An outstanding biochemical characteristic of neoplastic tissues is that despite ample oxygen supply, glycolysis is the dominant pathway for adenosine 5'-triphosphate (ATP) production, a phenomenon termed "the Warburg effect" (Warburg et al., 1927; Warburg, 1956). This aerobic glycolysis seems unexpected as one would imagine that cancer cells should have, given sufficient oxygen, adapted to utilize the complete oxidative phosphorylation to maximize ATP production. In addition, for producing same level of ATP, glycolysis would consume >15-fold more glucose, resulting in an addiction for glucose during active tumor growth. There must be a biological logic for cancer cells to prefer utilization of glycolysis for ATP production: they obtain and/or sustain growth advantage at the cost of an "addiction" to glycolysis. Mechanistically, there have been many hypotheses proposed to explain this phenomenon and two are more prominent: one is that by consuming excessive glucose, cancer cells may change the tumor's microenvironment to gain growth advantage over normal cells; the second is that, to sustain a dominant glycolysis process, cancer cells alter the expression or functions of glucose metabolic enzymes, which may have resulted in additional changes that promote cancer development (Vander Heiden et al., 2009). A growing body of evidence has supported both hypotheses and will be reviewed here.

#### **2. Altered glycolytic enzymes in cancer cells**

In cancer cells, the activities or expression levels of many enzymes participating in glucose metabolism are altered, those involved in glycolysis in particular. The glycolysis commonly refers to the reactions that covert glucose into pyruvate or lactate (Figure 1). Usually, one or more isoforms of glycolytic enzymes have altered expression patterns or activities in cancer cells, which was previously reviewed (Herling et al., 2011; Porporato et al., 2011).

Fig. 1. Glycolysis in cancer cells


 GLUT1, an isoform of **glucose transporters** (GLUTs) is overexpressed in many types of human malignancies, whereas the insulin-sensitive GLUT4 is downregulated in cancer cells. The imbalanced expression of GLUT1 versus GLUT4 in cancer cells may have contributed to the insulin-independent glucose uptake in cancer cells. In addition, GLUT3 was also reported to be overexpressed in cancer cells (Smith, 1999; Medina and

 HK-2, an isoform of **hexokinase** that is one of the three rate limiting glycolytic enzymes, is overexpressed in cancer cells and was shown to contribute to the Warburg effect. The high glycolytic rate characteristic of hypoxic solid tumors is attributed to the

 The expression level of the **glucose 6-phosphate isomerase** (GPI) has also been reported to be elevated in its mRNA level in different human cancer cell lines

overexpression of HK-2 (Mathupala et al., 2009; Wolf et al.).

Fig. 1. Glycolysis in cancer cells

(Funasaka et al., 2005).

Owen, 2002; Noguchi et al., 1998).


four LDH-M subunits, is an unfavorable prognostic factor for many human malignancies (Koukourakis et al., 2003; Koukourakis et al., 2005; Koukourakis et al., 2009). In addition, the glycolysis process in cancer cells is reportedly to be associated with hypermethylation of the *LDH-B* gene promoter, which is linked to gene silencing (Leiblich et al., 2006; Thangaraju et al., 2009).

 Plasma membrane **lactate transport** (LACT) is facilitated by the family of proton-linked moncarboxylate transporters (MCTs) or by SMCT1, a sodium coupled lactate transporter. The MCT4 isoform is upregulated in many cancer types. The expression of MCT2, an isoform mainly implicated in lactate import, is decreased in tumor cell lines. SMCT1, also implicated in lactate import, is downregulated in a number of cancer types including colon, thyroid, and stomach(Herling et al., 2011; Porporato et al., 2011).
