**3. Glucose metabolic pathways switched by oncogenes and tumor suppressors**

It has been long proposed that the altered expression or enzyme activities of glycolytic enzymes are regulated by oncogenes and tumor suppressor genes.


 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).

It has been long proposed that the altered expression or enzyme activities of glycolytic

 The expression of GLUT1 has been demonstrated to be controlled by the hypoxiainducible transcription factor HIF-1, c-Myc, and Akt (Chen et al., 2001; Osthus et al.,

 The gene encoding HK-2, but not HK-1, is known to be a transcriptional target of HIF-1(Rempel et al., 1996). It was later shown that HIF-1 cooperates with c-Myc to transactivate HK-2 under hypoxia (Kim et al., 2007). The phosphorylated form of HK-2 interacts with the voltage-dependent anion channel (VDAC) at the outer mitochondrial membrane (Bustamante and Pedersen, 1977; Nakashima et al., 1986; Gottlob et al., 2001). The interaction of HK-2 with VDAC interferes with the binding of the proapoptotic protein Bax to VDAC thus preventing the formation of the channel through which cytochrome c can escape from mitochondria to trigger apoptosis (Pastorino et al., 2002). Therefore, overexpression of HK-2 in cancer cells leads to a switch from HK-1 to HK-2 and offers a metabolic advantage by protecting cancer cells against

 Overexpression of GPI can be induced by HIF-1 and VEGF(Funasaka et al., 2005). The expression of PFK-2 genes in tumor cells is shown to be regulated by Ras and src (Yalcin et al., 2009) and that of PFKFB3 is demonstrated to be induced by HIF-1, cmyc, ras, src, and loss of function of p53 (Minchenko et al., 2002). Among the four PFK-2 genes, PFKFB3 is the most significantly induced in response to hypoxia. Hypoxia-induced PFK-2 activity of human PFKFB3 is further enhanced through phosphorylation of the serine 462 residue (Marsin et al., 2002). This phosphorylation process may involve AMP-activated protein kinase (AMPK) and Akt(Shaw and

 Although no evidence has suggested that the expression level of **Glyceraldehyde-3 phosphate dehydrogenase** (GAPDH) is altered in cancer cells, its expression has been demonstrated to be highly dependent on the proliferative state of the cells and can by

 The gene encoding ENOA is a target of, and its expression is upregulated by, c-Myc (Sedoris et al. 2010). Notably, a growing body of evidence has suggested that ENOA

regulated by HIF-1, p53, and c-jun(Colell et al., 2009; Colell et al., 2007).

**3. Glucose metabolic pathways switched by oncogenes and tumor** 

enzymes are regulated by oncogenes and tumor suppressor genes.

(Leiblich et al., 2006; Thangaraju et al., 2009).

**suppressors** 

2000; Rathmell et al., 2003).

apoptosis(Porporato et al., 2011).

Cantley, 2006; Yun et al., 2005).

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 is a tumor-associated antigen(Capello et al., 2011). In patients of many different cancer types, including pancreatic, leukemia, melanoma, head and neck, breast and lung, anti-ENOA autoantibodies have been detected(Capello et al., 2011). In pancreatic cancer patients, the anti-ENOA autoantibodies are directed against phosphorylated Serine 419(Tomaino et al., 2011). One study has shown that, in pancreatic cancer, ENOA elicits a CD4+ and CD8+ T cell response both in vitro and in vivo (Cappello et al., 2009). In pancreatic cancer patients, production of anti-ENOA IgG is correlated with the ability of T cells to be activated in response to ENOA(Cappello et al., 2009). In patients with oral squamous cell carcinoma, an HLA-DR8-restricted peptide (amino acid residues 321–336) of human ENOA recognized by CD4+ T cell has been identified (Kondo et al., 2002).


Therefore, activation of oncogenes and loss of tumor suppressors are believed to underlie the metabolic switch in cancer cells. Many cancer associated gene products are involved, including c-Myc, NF-kB, Akt, and multiple types of tyrosine kinase including epidermal growth factors (EGFs) and insulin-like growth factor 1 (IGF-1) receptor (Levine and Puzio-Kuter, 2010). Several pathways have been shown to be important for the regulation of glucose metabolism including the PI3K-AKT-mTOR and c-Myc pathways and both have HIF-1 as their downstream effector. Consistently, among the HIF-1 regulated genes, most are those encoding glycolytic enzymes (Semenza, 2003). The loss of PTEN and concurrent increase of Akt and mTOR lead to the HIF-1 activation and the Warburg effect (Arsham et al., 2002; Zundel et al., 2000).

Another oncogene, K-Ras, can alter glucose metabolism so as to provide tumor cells with a selective advantage. In cells with mutated K-Ras, GLUT1 is upregulated, leading to an augmented glucose uptake, glycolysis and lactate production. Interestingly, in these cells mitochondrial functions and oxidative phosphorylation are not compromised, which allows increased survival rate of the K-Ras mutant cells during glucose deprivation (Annibaldi and Widmann, 2010).

Loss of p53 functions also leads to the Warburg effect. As described above, p53 represses transcription of the genes encoding GLUT1 and 4, and induces transcription of the TIGAR gene, which in turn lowers the intracellular level of PFK/FBPase (Bensaad et al., 2006). In addition, p53 inhibits the PI3K-Akt-mTOR pathways. This appears to be mediated by the transcriptional targets of p53 including PTEN, IGF-binding protein 3, tuberous sclerosis protein TSC-2, and the beta subunit of AMPK (Feng et al., 2007). Conceivably, loss of p53 functions and subsequent loss of expression of these target genes lead to a high HIF level and establishment of the Warburg effect.
