Due to poor tumour-associated vasculature, tumour cells are subjected to a fluctuating microenvironment with periods of limited oxygen and glucose availability. Adaptive mechanisms to adverse microenvironments are important for tumour cell survival. The cyclooxygenase (COX)-2/prostaglandin E ₂ (PGE ₂ ) pathway has key roles in colorectal tumorigenesis. Although glucose is important as an energy source and in maintaining endoplasmic reticulum homeostasis, relatively little is known regarding how tumour cells adapt to the microenvironmental stress of reduced glucose availability. Here, we report the novel findings that glucose deprivation of colorectal tumour cells not only increases COX-2 expression but also decreases 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression, resulting in increased extracellular PGE ₂ . Furthermore, we have shown that PGE ₂ promotes tumour cell survival during glucose deprivation. Glucose deprivation enhances phosphoinositide 3-kinase/Akt activity, which has a role in both the up-regulation of COX-2 and down-regulation of 15-PGDH. Glucose deprivation also activates the unfolded protein response (UPR) resulting in elevated C/EBP-homologous protein (CHOP) expression. Interestingly, inhibiting CHOP expression by small interfering RNA during glucose deprivation attenuates the reduction in 15-PGDH expression. This is the first report linking activation of the UPR with a reduction in expression of tumour-suppressive 15-PGDH and may have implications for tumour cells’ ability to survive exposure to therapeutic agents that activate the UPR. Our data suggest that diverse microenvironmental stresses converge to regulate PGE ₂ as a common and crucial mediator of cell survival during adaptation to the tumour microenvironment and may lead to novel chemopreventive and therapeutic strategies.