Cyclooxygenase-2 in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) represents the most prevalent brain primary tumor, yet there is a lack of effective treatment. With current therapies, fewer than 5% of patients with GBM survive more than 5 years after diagnosis. Mounting evidence from epidemiological studies reveals that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is correlated with reduced incidence of GBM, suggesting that cyclooxygenase-2 (COX-2) and its major product within the brain, prostaglandin E2 (PGE₂), are involved in the development and progression of GBM. Here, we highlight our current understanding of COX-2 in GBM proliferation, apoptosis, invasion, angiogenesis, and immunosuppression by focusing on recent in vitro and in vivo experimental data. We also discuss the feasibility of COX-2 as a therapeutic target for GBM in light of the latest human studies.

Figure 1

Proposed cyclooxygenase-2 (COX-2) signaling pathways in glioblastoma multiforme (GBM). Responding to various stimuli, membrane-bound arachidonic acid is released and converted to the short-lived intermediate molecule prostaglandin H2 (PGH₂) by COX, which has two isoforms: constitutive COX-1 and inducible COX-2. PGH₂ is then quickly converted to five prostanoids: prostaglandin D2 (PGD₂), prostaglandin E2 (PGE₂), PGF_2α, prostacyclin (PGI₂), and thromboxane A2 (TXA₂), by tissue-specific prostanoid synthases. PGE₂ can be synthesized from PGH₂ by three isozymes [membrane-associated PGE synthase-1 (mPGES-1), mPGES-2, and cytosolic (c)PGES], among which mPGES-1 is traditionally considered inducible. Prostanoids exert their functions via acting on a suite of GPCRs: EP1, EP2, EP3, and EP4 for PGE₂; DP1 and DP2 for PGD₂; FP for PGF_2α; IP for PGI₂; and TP for TXA₂. COX-2-derived PGE₂ is proposed to mediate GBM cell proliferation and invasion, angiogenesis, immune suppression, and evasion via EP receptors. Only the major pathways are shown.

Figure 2

Chemical structures of nonselective cyclooxygenase (COX) inhibitors [nonsteroidal anti-inflammatory drugs (NSAIDs)] and selective COX-2 inhibitors (COXIBs) that have been widely tested in human glioblastoma multiforme (GBM) cell cultures, animal models, and human studies. Most of these COX inhibitors, except rofecoxib and NS398, are current US Food and Drug Administration (FDA)-approved drugs for other indications.

Figure 3

Crystal structure of arachidonic acid (a) and celecoxib (b) in the active site of the human cyclooxygenase-2 (COX-2) dimer. The molecular docking for the interaction between COX-2 and small molecules was generated by Discovery Studio software. The X-ray crystal structure of human COX-2 was obtained from the Protein Data Bank (PDB, ID: 5IKT) of the Research Collaboratory for Structural Bioinformatics (RCSB). The key active site residues of COX-2 important for binding are depicted as lines with atoms colored (carbon, grey; hydrogen, white; nitrogen, blue; and oxygen, red), and the binding molecules (arachidonic acid and celecoxib) are shown as ball-and-stick model with atoms colored (carbon, grey; hydrogen, white; nitrogen, blue; oxygen, red; and sulfur, yellow). The selectivity of celecoxib for COX-2 is largely determined by its sulfonamide functional group (see the highlights), which can fit into a side pocket of COX-2.

Figure 4

The development of intracranial tumors is enhanced by cyclooxygenase-2 (COX-2) and DNA-binding protein 1 (Id1). H&E staining was performed for coronal sections of mouse brains with xenograft tumors derived from either the human GBM cell line LN229 or COX-2/Id1-overexpressing cells. Brain tumors are denoted by arrows. Note that elevated COX-2 led to enhanced growth of intracranial tumors, which was recapitulated by Id1 overexpression in GBM cells. Scale bar = 2 mm. Reproduced, with permission, from [45].