Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E2–dependent activation of type II protein kinase A

Payner, Troy D.; Leaver, H.A.; Knapp, Brian I.; Whittle, Ian R.; Trifan, Ovidiu C.; Miller, Steven T.; Rizzo, Maria Teresa

doi:10.1158/1535-7163.mct-05-0548

Cited by 43 publications

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References 41 publications

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“…33 The same discrepancy can be observed in cell culture. mPGES-1 could namely promote the growth of a human glioma cell line 34 through PGE 2 extracellular pathway, whereas we showed that it was a proapoptotic enzyme in human brain tumor primary cultures through the activation of Bax by intracellular PGE 2 and subsequent caspase activity. 8 We confirmed that this discrepancy was linked to PGE 2 localization, as the pharmacological sequestration of PGE 2 was sufficient to induce apoptosis.…”

Section: Discussionmentioning

confidence: 65%

Prostaglandins antagonistically control Bax activation during apoptosis

et al. 2010

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The Bax protein (Bcl-2-associated X protein) is pivotal for the apoptotic process. Bax, which resides in an inactive form in the cytosol of healthy cells, is activated during the early stages of apoptosis and becomes associated with mitochondria through poorly understood mechanisms. In this study, we show that a family of bioactive lipids, namely prostaglandins, regulates Bax-dependent apoptosis. The prostaglandin E 2 (PGE 2 ) or its derivative PGA 2 binds to Bax, induces its change of conformation, and thereby triggers apoptosis. A cysteine present in the loop between the two transmembrane a-helices of Bax, Cys126 is critical for its activation. PGD 2 inhibits PGE 2 binding to Bax and PGE 2 -induced apoptosis, as well as cell death induced by staurosporine and UV-B in various cell lines. This result is consistent with the fact that apoptosis is accompanied during these treatments by an increase in PGE 2 . This process is distinct, yet cooperative, from that involving the BH3-only protein Bid. Our results establish that the PGE 2 /PGD 2 balance is involved in a new early mechanism of control in the activation of Bax during apoptosis. Cell Death and Differentiation (2011) 18, 528-537; doi:10.1038/cdd.2010.128; published online 22 October 2010Members of the Bcl-2 (Bcl-2-associated X protein) family of proteins determine both the initiation and the execution of mitochondrial outer membrane permeabilization (MOMP) and the subsequent apoptosis. These proteins share a similar solution structure, and are subdivided into two groups: antiapoptotic proteins (e.g., Bcl-2, Bcl-Xl, Bcl-W and Mcl-1) and proapoptotic proteins, which control apoptosis through complex interaction with each other. Proapoptotic proteins are further subdivided into multidomain proteins (namely, Bax, Bak and Bok) and BH3-only proteins (e.g., Bim, Bad, Bid, Puma or Noxa) whose homology with Bcl-2 is limited to the BH3 domain. BH3-only proteins function as upstream sensors that selectively respond to specific signals and promote the proapoptotic function of Bax and/or Bak. Both in vivo and in vitro experiments have proved that the conformation of monomeric Bax/Bak change upon induction of apoptosis, leading to their oligomerization in the mitochondrial membrane and MOMP. [1][2][3] How Bax and Bak are activated is a matter of debate. 2,4 A widely accepted model proposes that some BH3-only proteins called 'activators' (tBid, Bim and Puma) induce the Bax/Bak apoptotic conformational change through transient physical interaction in a 'hit and run' manner. Another group named 'enabler' (also called derepressor or sensitizer) can release Bax and Bak from antiapoptotic proteins, which in turn trigger MOMP. [1][2][3] The existence of a direct interaction of Bax/Bak with BH3-only proteins has been challenged, suggesting the existence of alternative mechanisms responsible for the activation of Bax or Bak. A change in pH or temperature has also been shown to facilitate the transition between the inactive and active states of Bax, supporting a role for nonprotein...

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Section: Discussionmentioning

confidence: 65%

Prostaglandins antagonistically control Bax activation during apoptosis

et al. 2010

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“…Gathering this data from our study and the others mentioned, we have reason to believe that mPGES1 is expressed and produced in the five glioma cell lines A-172, U-251MG, U-87MG, U-138MG, and T-98G. Payner et al (2006) demonstrated that blocking mPGES1 activity and expression inhibited the release of PGE 2 and decreased cellular proliferation. This implies that mPGES1 can regulate glioma growth through a PGE 2 -dependent pathway, making mPGES1 a valuable target for treatments.…”

Section: The Confirmed Presence Of the Pgd 2 Synthesis Pathwaysupporting

confidence: 72%

“…However, they did not detect mPGES1 in U-138MG (Payner et al, 2006). Using immunohistochemistry, we observed a strong staining of mPGES1 in U-87MG, U-251MG and A172.…”

Section: The Confirmed Presence Of the Pgd 2 Synthesis Pathwaymentioning

confidence: 55%

Analysis of how the production and activity of PGD2 affects glioma cell lines.

Ferreira¹

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Ferreira MT. Analysis of how the production and activity of PGD 2 affects glioma cell lines.[Masters thesis (Cell and Tissue Biology)]. São Paulo: Instituto de Ciências Biomédicas, Universidade de São Paulo; 2014.The World Health Organization classifies glioblastoma (GBM) as a type IV astrocytoma, making it one of the most fatal tumors that exists. Despite the advances in chemotherapy, surgery, and radiation treatments that improve a patient's length of survival, the overall trajectory of the disease remains unchanged. It has been shown that GBM cells produce significant levels of prostaglandins, including prostaglandin D2 (PGD 2 ). PGD 2 possesses pro-and anti-tumorigenic properties. Hence, a more complete understanding of PGD 2 activity in GBM could yield more effective treatments against GBM. Through techniques like RT-PCR, immunohistochemistry, and HPLC tandem mass spectrometry, we were able to confirm the capacity for synthesis of PGD 2 in GBM cell lines. We treated GBM cell lines with various concentrations of exogenous PGD 2 over 72 hours and observed its effects on cell count, apoptosis, mitosis and viability. Our results suggest that PGD 2 possesses contradictory functions in GBM depending on concentration (μM PGD 2 vs. nM PGD 2 ) and receptor activation.

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“…An increased expression of mPGES-1 in the tissues of patients of brain cancer has also been reported from another group in a subset of human glioblastoma multiforme (GBM) tumors, the most common form of adult brain cancer, astrocytoma and high-risk neuroblastoma. [45][46][47] An activated COX/mPGES-1/PGE 2 pathway has been identified in 11q-deleted neuroblastoma with high expression of mPGES-1, and elevated levels of PGE 2 as compared with low-risk tumors. Analysis of expression cohorts revealed a worse outcome for high-risk patients (INSS stage 4) with high mPGES-1 expression.…”

Section: Role Of Mpges-1 In Brain Cancermentioning

confidence: 99%

The Role of mPGES-1 in Inflammatory Brain Diseases

Ikeda‐Matsuo

2017

Biological & Pharmaceutical Bulletin

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Prostaglandin E 2 (PGE 2 ) has been thought to be an important mediator of inflammation in peripheral tissues, but recent studies clearly show the involvement of PGE 2 in inflammatory brain diseases. In some animal models of brain disease, the genetic disruption and chemical inhibition of cyclooxygenase (COX)-2 resulted in the reduction of PGE 2 and amelioration of symptoms, and it had been thought that PGE 2 produced by COX-2 may be involved in the progression of injuries. However, COX-2 produces not only PGE 2 , but also some other prostanoids, and thus the protective effects of COX-2 inhibition, as well as severe side effects, may be caused by the inhibition of prostanoids other than PGE 2 . Therefore, to elucidate the role of PGE 2 , studies of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE 2 synthesis, have recently been an active area of research. Studies from mPGES-1 deficient mice provide compelling evidence for its role in a variety of inflammatory brain diseases, such as ischemic stroke, Alzheimer's disease and epilepsy, and clues for developing new therapeutic treatments for brain diseases by targeting mPGES-1. Considering that COX inhibitors may non-selectively suppress the production of many types of prostanoids that are essential for normal physiological functioning of the brain and peripheral tissues, as well as induce gastro-intestinal, renal and cardiovascular complications, mPGES-1 inhibitors are expected to be injury-selective and have fewer side-effects when treating human brain diseases. Thus, this paper focuses on recent studies that have demonstrated the involvement of mPGES-1 in pathological brain diseases.

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Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E2–dependent activation of type II protein kinase A

Cited by 43 publications

References 41 publications

Prostaglandins antagonistically control Bax activation during apoptosis

Prostaglandins antagonistically control Bax activation during apoptosis

Analysis of how the production and activity of PGD2 affects glioma cell lines.

The Role of mPGES-1 in Inflammatory Brain Diseases

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