Drug Discovery
increasing the expression key components of the glutamine metabolic pathway43 and to enhance oxidative metabolism of glucose via increased pyruvate dehydrogenase44 and lactate dehydroge- nase expression/activity45. HIF111,46-48, a tran- scription factor which can be upregulated in hypoxic conditions or by enhanced oncogenic (ie Myc49,50) or decreased tumour suppressor (ie Von Hippel-Lindau51) function is also known to upregulate the expression of many metabolic enzymes including glucose transporters (GLUT448), metabolic regulators (PFKFB352,53, PFKFB452, pyruvate dehydrogenase kinase (PDK1)44,54) and glycolytic enzymes (hexokinase- 2 (HK2)44, PK-M255, lactate dehydrogenase (LDHa)56, monocarboxylate transporter 4 (MCT4)57). This suggests that metabolic adapta- tions also play a role in maintaining tumour growth and survival in hypoxic conditions. Akt also increases glycolysis by increasing glucose transporter expression32 and facilitating hexoki- nase translocation to the mitochondria where it functions to initiate glycolytic flux34,58. The tumour suppressor protein p5359,60 has also been shown to regulate expression of various glycolytic proteins including upregulation of hexokinase and of a protein called TIGAR which acts as a negative regulator of glycolysis61,62. p53 also promotes oxidative phosphorylation via upregulation of SCO263 and suppresses glycolysis via expression of PTEN, a negative regulator of the PI3K path- way64. Therefore, while loss of p53 may drive acquisition of the glycolytic phenotype it will be important to understand metabolic regulation in p53 wild type and mutant tumours. Understanding the interplay between oncogenes and tumour suppressors and metabolic pathways will be key to deciphering how metabolism inte- grates into tumour initiation and progression and in looking for potential therapeutic targets with clear clinical stratification. The rest of this review will take a stripped-down look at metabolism and introduce a couple of potential metabolism targets which are currently being extensively investigated both by academia and industry.
The basic stages of glucose and glutamine metabolism in cancer At its simplest level the complex process of glucose and glutamine metabolism can be split into four key phases (Figure 2). The first phase is the uptake of these essential metabolic substrates into the cell via transporter proteins. The process actively imports high concentrations of glucose or gluta- mine into the cell ready for utilisation and in can-
Drug Discovery World Fall 2011
cers predominantly involves the transporters
Table 1: Control of metabolic processes by oncogenes and tumour suppressor genes
GLUT1 and GLUT4 for glucose65 and ASCT2(SLC1A5) for glutamine66. GLUT1 and GLUT4 have been found to be overexpressed in many cancers and to be upregulated by ras and myc signalling65,67. Currently there are no clear inhibitors of GLUT1/4 published although the natural dihydrochalcone, Phloretin is reported to have GLUT inhibitory activity and be effective in inducing apoptosis in in vivo cancer models68. ASCT2 is also overexpressed in some tumours69 and reported to be directly upregulated by myc18,70 although as yet no clear inhibitors of this transporter have been reported. The oncogenic upregulation of glucose and/or glutamine trans- porters in cancer helps to explain how tumours adapt to facilitate their increased reliance on glu- cose and/or glutamine and how tumours can accu- mulate high levels of these metabolites. The next step is the initial processing of these imported metabolises by conversion into the first metabolic product which can act as an entry sub- strate into the main metabolic processing path- ways. This conversion acts to trap the imported metabolite within the cell and to commit it to fur- ther processing into downstream intermediates as well as shift equilibrium balances to allow the influx of more glucose or glutamine to meet the
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