Colon tumour cells increase PGE2 by regulating COX-2 and 15-PGDH to promote survival during the microenvironmental stress of glucose deprivation

Abstract

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.

Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis

“…The loss of 15-PGDH expression may also result from impaired TGF-β signaling, a common event in colon and gastric cancers (42)(43)(44). While published data support the concept that 15-PGDH plays a direct role in controlling epithelial cell proliferation and colony-forming capacity, it has also been suggested that disruption of 15-PGDH expression may be a required or important step for cancer cell adaptation to the hypoxic tumor microenvironment and may promote survival under the microenvironmental stress of glucose deprivation (11,15). Furthermore, there is also a link between tumor-induced immunosuppression and a deficiency of 15-PGDH expression, with loss of 15-PGDH in tumor-infiltrating myeloid cells leading to immune evasion (45).…”

“…The human PGDH gene is located on chromosome 4 and encodes a 29-kDa protein. 15-PGDH is highly expressed in normal colon epithelia but the expression is decreased in colon cancers (12)(13)(14)(15). 15-PGDH has a demonstrated tumor suppressor activity in lung cancer and breast cancer (16,17), and overexpression of 15-PGDH inhibits growth of colon tumor xenografts in immune-deficient mice (13).…”

“…15-PGDH is highly expressed in normal colon epithelia but the expression is decreased in colon cancers (12)(13)(14)(15). 15-PGDH has a demonstrated tumor suppressor activity in lung cancer and breast cancer (16,17), and overexpression of 15-PGDH inhibits growth of colon tumor xenografts in immune-deficient mice (13). Expression of 15-PGDH is induced in colon epithelial cells by treatment with TGF-β, a cytokine known to activate an important tumor suppressor pathway in colon cancer (13,18,19).…”

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

“…Stress also activates the unfolded protein response system that ultimately activates survival proteins such as the heat shock protein Hsp90 (Saito et al, 2009). Additionally, prolonged hypoglycaemic stress has been known to contribute to oncogenic mutation (Yun et al, 2009) and activate survival pathways, including the PI3K/AKT pathway (Roberts et al, 2011). Given these survival phenotypes, it is reasonable to hypothesize that low extracellular glucose levels could increase drug resistance.…”

Expression of PGDH Correlates with Cell Growth in Both Esophageal Squamous Cell Carcinoma and Adenocarcinoma

“…Mutation of PGDH was associated with high level of prostaglandin E2 and congenital osteoarthricular hypertrophy (cite) (Thill et al, 2010;Young et al, 2013). Furthermore, high physiological level of PGDH was found in various normal human epithelial tissue, including lung (Ding et al, 2005;Tai et al, 2007;Li et al, 2014), colon (Chi et al, 2009;Roberts et al, 2011), stomach and breast (Brocklehurst et al, 1986). The expression of PGDH in normal human tissue helps control of the level of prostaglandins, which are produced by protumorigenic enzymes including cyclooxygenase-2.…”