Prostaglandin E2 Regulates the Complement Inhibitor CD55/Decay-accelerating Factor in Colorectal Cancer

Vijaykumar R Holla,Dingzhi Wang,Joanne R Brown,Jason R Mann,Sharada Katkuri,Raymond N Dubois

doi:10.1074/jbc.m407403200

Vijaykumar R Holla, Dingzhi Wang + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m407403200

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Abstract

Cyclooxygenase-derived prostaglandin E(2) (PGE(2)) stimulates tumor progression by modulating several proneoplastic pathways. The mechanisms by which PGE(2) promotes tumor growth and metastasis through stimulation of cell migration, invasion, and angiogenesis have been fairly well characterized. Much less is known, however, about the molecular mechanisms responsible for the immunosuppressive effects of PGE(2). We identified PGE(2) target genes and subsequently studied their biologic role in colorectal cancer cells. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE(2) treatment of LS174T colon cancer cells. Analysis of PGE(2)-mediated activation of the DAF promoter employing 5'-deletion luciferase constructs suggests that regulation occurs at the transcriptional level via a cyclic AMP/protein kinase A-dependent pathway. Nonsteroidal anti-inflammatory drugs blocked DAF expression in HCA-7 colon cancer cells, which could be restored by the addition of exogenous PGE(2). Finally, we observed an increase in DAF expression in the intestinal mucosa of Apc(Min+/-) mice treated with PGE(2) in vivo. In summary, these results indicate a novel immunosuppressive role for PGE(2) in the development of colorectal carcinomas.

Highlights

Immune evasion represents an important mechanism by which cancer cells survive in a hostile environment
prostaglandin E2 (PGE2) treatment increased DAF protein levels by 4 h (2-fold), and DAF expression remained elevated for 24 h (Fig. 1B)
Adding PGE2 induced DAF expression in a dose-dependent manner (Fig. 1C). mRNA levels were maximal at 2 ␮M (8-fold), whereas protein levels peaked at 10 ␮M (11-fold) PGE2 (Fig. 1D)

Summary

Introduction

Immune evasion represents an important mechanism by which cancer cells survive in a hostile environment. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE2 treatment of LS174T colon cancer cells. Previous reports suggest that tumor cells induce CRPs as an effective mechanism to evade immune surveillance and complement-mediated cytotoxicity.

Results

Conclusion