Epithelial cells in the gastrointestinal tract have a highly turnover rate and play essential
roles in maintaining gut homeostasis. In the current studies, both types of cell death,
apoptosis and necroptosis, in epithelial cells may be attenuated by enteral glucose
uptake. Normal SGLT1-mediated anti-apoptotic signaling may prevent epithelial cell
death from ischemic stress in small intestine, but abnormal expression of GLUTs and
enhanced glycolytic metabolism may also block hypoxic death in colorectal cancer
cells.
The benefits of early enteral nutrition (EN) over parenteral supplementation and of
preoperative oral carbohydrate loading (CHO) compared to overnight fasting have
gained much attention in nutrition therapy nowadays (Fearon et al., 2005; Martindale et
al., 2006). The advantage of early EN and CHO may also involve SGLT1-mediated
nutritive and non-nutritive functions. On the other hand, drug resistance and metastatic
transition in colorectal cancer are associated to adaptive responses to hypoxic
microenvironment and HIF1-targeted increase of glucose transporters and glycolytic
enzymes (Denko, 2008; Chiacchiera et al., 2009; Marin-Hernandez et al., 2009; Zeng et
al., 2010; Rapisarda et al., 2012). Our study provided novel cancer killing strategies to
be based on modulation of anaerobic glucose metabolism and glycolytic pyruvate in
death resistance by targeting site-specific glucose transporters. The combinational
strategies with glucose- or pyruvate-targeted therapy may overcome the resistance to
antiangiogesis or hypoxic stress.
In conclusion, the understanding of hypoxic-induced cell death pathways and
resistance mechanisms conferred by glucose may benefit the development of novel
therapeutic interventions targeting glucose transporters for treating gastrointestinal
disease caused by abnormal cell death.
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