COX2

Official Full Name

cytochrome c oxidase subunit II

Synonyms

cCOII;

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Detailed Information

The PTGS2 gene, located on human chromosome 1q31.1, encodes cyclooxygenase-2 (COX-2), one of the two isoenzymes in the cyclooxygenase family responsible for the rate-limiting step in prostaglandin biosynthesis, alongside PTGS1. A key feature of PTGS2 is its inducible expression pattern. Unlike PTGS1, which is constitutively expressed in most tissues to maintain baseline prostaglandin levels, PTGS2 is expressed at very low or undetectable levels under normal conditions. Upon stimulation by proinflammatory cytokines, growth factors, tumor promoters, endotoxins, or physical injury, PTGS2 transcription is rapidly and robustly upregulated. This inducibility is mediated by multiple transcription factor binding sites in its promoter region, including NF-κB, CREB, and C/EBP, enabling PTGS2 to act as a critical molecular node linking pathological stimuli to downstream inflammatory and proliferative responses.

Biological Significance

PTGS2 functions as a central hub for cellular stress responses, translating diverse pathophysiological stimuli into the biosynthesis of specific lipid mediators. It is a bifunctional enzyme, possessing both cyclooxygenase and peroxidase activities. The cyclooxygenase activity converts arachidonic acid to prostaglandin G2 (PGG2), which is subsequently reduced by the peroxidase activity to prostaglandin H2 (PGH2). PGH2 is the common precursor for all series-2 prostaglandins and thromboxanes, including PGE2, PGI2, PGD2, and TXA2, which act through autocrine or paracrine signaling via G-protein-coupled receptors, regulating complex cellular processes.

Figure 1. Roles of PTGS2/COX2-PGE2 in different inflammatory situations. (Martín-Vázquez E, et al., 2023)

During acute inflammation, inducible PTGS2 is the primary source of proinflammatory prostaglandins such as PGE2, mediating vasodilation, increased vascular permeability, pain sensitization, and fever, which constitute classic signs of inflammation.

Beyond inflammation, PTGS2 is involved in cell proliferation, differentiation, and angiogenesis. It is induced during tissue repair, wound healing, and embryonic development, promoting cell survival, proliferation, and neovascularization through prostaglandin production. However, this function can be hijacked in cancer: many tumor cells maintain high PTGS2 expression to enhance proliferation, inhibit apoptosis, increase invasiveness, and induce tumor angiogenesis, while shaping an immunosuppressive tumor microenvironment. Recent research also highlights PTGS2's role in complex lipid mediator biosynthesis, utilizing different polyunsaturated fatty acid substrates and potentially generating pro-resolving mediators such as resolvins, indicating its involvement in inflammation resolution as well as initiation. Thus, PTGS2's biological role is highly context-dependent, acting as both a mediator of acute defense and repair and, when dysregulated, a promoter of chronic inflammatory diseases and tumor progression.

Clinical Relevance

PTGS2's clinical significance is most directly linked to its role as a target of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin. Traditional non-selective NSAIDs inhibit both PTGS1 and PTGS2, blocking prostaglandin synthesis to achieve anti-inflammatory, analgesic, and antipyretic effects. Inhibition of PTGS1, however, contributes to gastrointestinal ulcers and bleeding, as PTGS1-derived prostaglandins maintain gastric mucosal protection and platelet function. This led to the development of selective COX-2 inhibitors, designed to retain anti-inflammatory efficacy while minimizing gastrointestinal toxicity. Despite clinical success, long-term use of certain highly selective COX-2 inhibitors was found to increase cardiovascular risk, highlighting the delicate balance of prostaglandins, particularly between PGI2 and TXA2, in cardiovascular homeostasis.

In oncology, epidemiological and clinical studies demonstrate PTGS2 overexpression in colorectal, breast, lung, and other cancers, often correlating with tumor aggressiveness, angiogenesis, and poor prognosis. PTGS2 is therefore a target for chemoprevention and adjunctive cancer therapy, with long-term NSAID or aspirin use shown to reduce the incidence of certain cancers. Challenges remain, including cardiovascular safety and heterogeneity of patient response. Current research focuses on identifying responsive patient subgroups, understanding PTGS2 interactions with oncogenic pathways, and developing tumor-targeted inhibitor delivery systems.

Additionally, in neurodegenerative diseases such as Alzheimer's disease, inflammation and PTGS2 expression may contribute to pathology, although the precise role and therapeutic potential remain under investigation. In summary, PTGS2 research has transformed our understanding of inflammation and cancer and continues to influence therapeutic strategies, with future clinical translation dependent on precise mapping of PTGS2's complex biological networks in disease-specific contexts.

References

Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J. 1998;12(12):1063–1073.
Wang D, DuBois RN. Eicosanoids and cancer. Nat Rev Cancer. 2010;10(3):181–193.
Wang D, Xia D, Dubois RN. The Crosstalk of PTGS2 and EGF Signaling Pathways in Colorectal Cancer. Cancers (Basel). 2011 Oct 14;3(4):3894-908.
Martín-Vázquez E, Cobo-Vuilleumier N, López-Noriega L, et al. The PTGS2/COX2-PGE₂ signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus. Int J Biol Sci. 2023 Aug 6;19(13):4157-4165.

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