Journal Article

Colon tumour cells increase PGE<sub>2</sub> by regulating COX-2 and 15-PGDH to promote survival during the microenvironmental stress of glucose deprivation

Heather R. Roberts, Helena J.M. Smartt, Alexander Greenhough, Amy E. Moore, Ann C. Williams and Christos Paraskeva

in Carcinogenesis

Volume 32, issue 11, pages 1741-1747
Published in print November 2011 | ISSN: 0143-3334
Published online September 2011 | e-ISSN: 1460-2180 | DOI:
Colon tumour cells increase PGE2 by regulating COX-2 and 15-PGDH to promote survival during the microenvironmental stress of glucose deprivation

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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 E2 (PGE2) 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 PGE2. Furthermore, we have shown that PGE2 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 PGE2 as a common and crucial mediator of cell survival during adaptation to the tumour microenvironment and may lead to novel chemopreventive and therapeutic strategies.

Journal Article.  5449 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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