Dataset Information

The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas.

ABSTRACT: The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2-derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4-PI3K-Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4-PI3K-Akt-NFκB-PD-1 signaling pathway. In contrast, inhibiting the COX-2-PGE2-EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion.

Prevention relevance

These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs.

SUBMITTER: Wei J

PROVIDER: S-EPMC9064954 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas.

Wei Jie J Zhang Jinyu J Wang Dingzhi D Cen Bo B Lang Jessica D JD DuBois Raymond N RN

Cancer prevention research (Philadelphia, Pa.) 20220501 5

The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2-derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4-PI3K-Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor ...[more]

PMID: 35121582

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Project description:Enteric caliciviruses in the genera Norovirus and Sapovirus are important pathogens that cause severe acute gastroenteritis in both humans and animals. Cyclooxygenases (COXs) and their final product, prostaglandin E2 (PGE2), are known to play important roles in the modulation of both the host response to infection and the replicative cycles of several viruses. However, the precise mechanism(s) by which the COX/PGE2 pathway regulates sapovirus replication remains largely unknown. In this study, infection with porcine sapovirus (PSaV) strain Cowden, the only cultivable virus within the genus Sapovirus, markedly increased COX-2 mRNA and protein levels at 24 and 36 h postinfection (hpi), with only a transient increase in COX-1 levels seen at 24 hpi. The treatment of cells with pharmacological inhibitors, such as nonsteroidal anti-inflammatory drugs or small interfering RNAs (siRNAs) against COX-1 and COX-2, significantly reduced PGE2 production, as well as PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We observed that pharmacological inhibition of COX-2 dramatically increased NO production, causing a reduction in PSaV replication that could be restored by inhibition of nitric oxide synthase via the inhibitor N-nitro-l-methyl-arginine ester. This study identified a pivotal role for the COX/PGE2 pathway in the regulation of NO production during the sapovirus life cycle, providing new insights into the life cycle of this poorly characterized family of viruses. Our findings also reveal potential new targets for treatment of sapovirus infection. Sapoviruses are among the major etiological agents of acute gastroenteritis in both humans and animals, but little is known about sapovirus host factor requirements. Here, using only cultivable porcine sapovirus (PSaV) strain Cowden, we demonstrate that PSaV induced the vitalization of the cyclooxygenase (COX) and prostaglandin E2 (PGE2) pathway. Targeting of COX-1/2 using nonsteroidal anti-inflammatory drugs (NSAIDs) such as the COX-1/2 inhibitor indomethacin and the COX-2-specific inhibitors NS-398 and celecoxib or siRNAs targeting COXs, inhibited PSaV replication. Expression of the viral proteins VPg and ProPol was associated with activation of the COX/PGE2 pathway. We further demonstrate that the production of PGE2 provides a protective effect against the antiviral effector mechanism of nitric oxide. Our findings uncover a new mechanism by which PSaV manipulates the host cell to provide an environment suitable for efficient viral growth, which in turn can be a new target for treatment of sapovirus infection.

Dataset Information

The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas.

Prevention relevance

Publications

The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas.

Similar Datasets

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