stem cells, the CSCs reside in niches, a microenvironment that is capable of maintaining a balance between self-renewal and differentiation. The major difference between the niches of normal and CSCs is the predominance of proliferative signals in the latter. The tumour niche has been characterized to involve hypoxia and hypoglycaemia as a result of glycolysis. Indeed, hypoxia has been reported to generate CSCs in tumours, which can lead to a drug-resistant phenotype. British Journal of Pharmacology 173 970979 973 BJP B Bhattacharya et al. In addition to hypoglycaemia, the Notch signalling pathway is typically associated with `stemness’ and is also affected by glucose. Breast cancer xenografts with high Notch activity have been demonstrated to grow better in glucose-deprived conditions compared with tumours with low Notch activity. However, this study did not determine whether the survival advantage of the tumours was due to the initiation of CSCs. Further evidence supporting the role of glycolysis in generating CSCs comes from PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19821824 the observation that PKM2 via TIGAR and p53 interact with `stemness’ transcription factors, for example, Oct4. The acidic microenvironment created by increased glycolysis in tumours is also considered to provide a favourable niche for CSCs. Studies have shown that trastuzumab-resistant cells have higher levels of HSF1, and inhibition of HSF1 sensitizes cells to trastuzumab. This was attributed to an increase in glycolysis by HSF1, and the combination of oxamate and trastuzumab interacted synergistically in the resistant cells. Energy sensors The tumour suppressor STK11 encodes LKB1, a serine threonine kinase regarded as a `master kinase’ 
for regulating essential cellular functions. Such functions include energy conservation, cell polarity and various metabolic processes. AMPK is one of the major substrates of LKB1 and is also a central energy-sensing kinase. A reduction in A and increase in TP AMP activate AMPK. Activated AMPK in turn inhibits mTOR signalling and protein translation for conserving energy. Furthermore, AMPK activation leads to cell cycle arrest as a result of p53 stabilization and activation of cyclin-dependent kinase inhibitors p21 and p27. During nutrient-deprived states, cancer cells, by initiating AMPK signalling, halt energy-consuming processes. Under normal physiological conditions, such cells undergo apoptotic cell death. However, cancer cells under nutrient deprivation or hypoglycaemic conditions avoid cell death through the induction of autophagy. A key regulator of autophagy is mTOR, while apoptosis is controlled intrinsically by the mitochondrial machinery. Inhibition of mTOR as a result of AMPK activation activates autophagy, thus promoting cell survival. It is believed that autophagy promotes cell survival by recycling intracellular organelles to produce energy. Autophagic cells are A-83-01 web highly resistant to treatment with both conventional and targeted agents, therefore providing a connection between glycolysis and drug resistance. Nonetheless, prolonged autophagy and AMPK activation can also lead to additional signalling changes, which ultimately will lead to cell death. Glycolysis and hypoglycaemia An obvious consequence of increased glycolysis is an increased utilization of glucose by tumour cells. The increased glucose consumption in turn creates a hypoglycaemic microenvironment or a nutrient-deprived state. This relationship of the tumour with its microenvironment can be envisaged as
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