Journal
ONCOGENE
Volume 26, Issue 21, Pages 3006-3019Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210113
Keywords
colorectal cancer; cyclic AMP; EP receptor; prostaglandin E-2
Funding
- Medical Research Council [G116/146] Funding Source: Medline
- MRC [G116/146] Funding Source: UKRI
- Medical Research Council [G116/146] Funding Source: researchfish
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The predominant product of cyclooxygenase ( COX) activity in the colon, prostaglandin ( PG) E-2 promotes intestinal tumorigenesis. Expression of the PGE(2) receptor EP4 is upregulated during colorectal carcinogenesis. Therefore, we investigated the role of elevated PGE(2)-EP4 receptor signalling in the protumorigenic activity of PGE2 by increasing EP4 receptor expression in HT-29 human colorectal cancer ( CRC) cells ( HT-29-EP4) by stable transfection. Elevated PGE(2)-induced EP4 receptor activity in HT-29 cells increased resistance to spontaneous apoptosis and promoted anchorage-independent growth, but had no effect on proliferation of HT-29-EP4 cells. EP4 receptor activation by PGE(2) in HT-29-EP4 cells also led to development of fluid-filled cysts, which was associated with increased tight junction protein ( occludin and zonula occludens-1) expression. Overexpression of the EP4 receptor in HT-29 cells led to basal EP4 receptor signalling in the absence of exogenous PGE(2), which was explained by autocrine activity of endogenous, COX-2-derived PGE(2) and constitutive, ligand-independent EP4 receptor activity. The predominant signalling pathway mediating antiapoptotic activity downstream of PGE(2)-EP4 receptor activation in HT-29-EP4 cells was elevation of cyclic adenosine monophosphate ( cAMP) levels, which was associated with phosphorylation of cAMP-response element binding protein. EP4 receptor activation led to a small increase in phosphorylated extracellular signal-regulated kinase ( ERK) 2 protein levels but inhibition of ERK phosphorylation did not abrogate the antiapoptotic activity of PGE(2). However, PGE(2)-EP4 receptor signalling did not lead to trans-activation of the epidermal growth factor receptor in HT-29 cells. Inhibition of protumorigenic PGE(2)-EP4 receptor signalling represents a potential strategy for anti-CRC therapy that may avoid the toxicity associated with systemic COX inhibition.
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