Eicosanoids and cancer

Wang, Dingzhi; DuBois, Raymond N.

doi:10.1038/nrc2809

Cited by 1,518 publications

(1,622 citation statements)

References 139 publications

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“…26 To give a few examples, PGE 2 , the main prostaglandin, has been reported to inhibit apoptosis in colon cancer 10 and in radiation-treated epithelial cells 11 through mechanisms involving the proteins of the Bcl-2 family. On the other hands, PGE 2 has been shown to induce apoptosis in human lymphocytes and in fibroblasts through multiple pathways.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Prostaglandins antagonistically control Bax activation during apoptosis

et al. 2010

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“…22 Finally, most reports claim that PGE 2 skews the immune response towards a T h 2 response, although conflicting results have been reported. 16,23,24 Notably, the alleged Tcell stimulatory effect of PGE 2 has only been shown for CD4 1 T h 1 cells in vivo and in models of autoimmunity. In the current investigation, we show that a large fraction of blood CD4 1 and CD8 1 T cells were positive for the T h 1 marker T-bet, indicating that COX-2 inhibition and GM-CSF immunotherapy induce a T h 1 response.…”

Section: Short Reportmentioning

confidence: 99%

Intratumoral COX‐2 inhibition enhances GM‐CSF immunotherapy against established mouse GL261 brain tumors

Eberstål

Sandén

Fritzell

et al. 2013

Intl Journal of Cancer

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Immunotherapy has shown effectiveness against experimental malignant brain tumors, but the clinical results have been less convincing most likely due to immunosuppression. Prostaglandin E 2 (PGE 2 ) is the key immunosuppressive product of cyclooxygenase-2 (COX-2) and increased levels of PGE 2 and COX-2 have been shown in several tumor types, including brain tumors. In the current study, we report enhanced cure rate of mice with established mouse GL261 brain tumors when immunized with granulocyte macrophage-colony stimulating factor (GM-CSF) secreting tumor cells and simultaneously treated with the selective COX-2 inhibitors parecoxib systemically (5 mg/kg/day; 69% cure rate) or valdecoxib intratumorally (5.3 mg/kg/day; 63% cure rate). Both combined therapies induced a systemic antitumor response of proliferating CD4 1 and CD8 1 T cells, and further analysis revealed T helper 1 (T h 1) cell supremacy. The GL261 tumor cell line produced low levels of PGE 2 in vitro, and co-staining at the tumor site demonstrated that a large fraction of the COX-2 1 cells were derived from CD45 1 immune cells and more specifically macrophages (F4/80 1 ), indicating that tumor-infiltrating immune cells constitute the primary source of COX-2 and PGE 2 in this model. We conclude that intratumoral COX-2 inhibition potentiates GM-CSF immunotherapy against established brain tumors at substantially lower doses than systemic administration. These findings underscore the central role of targeting COX-2 during immunotherapy and implicate intratumoral COX-2 as the primary target.The prognosis for patients with high-grade brain tumors remains poor despite extensive treatment, including surgery, radiotherapy and chemotherapy. 1,2 Treatment failure is mainly ascribed to the infiltrative capacity of the tumor cells, which form tumor microsatellites deep in the normal brain parenchyma. Immunotherapy represents a novel approach that could target these residual tumor cells and has been shown to be safe and induce prolonged survival in clinical trials. [3][4][5] However, the therapeutic effect of immunotherapy is often down-regulated because of immunosuppression.Prostaglandin E 2 (PGE 2 ) constitutes a key suppressive mediator and is synthesized from arachidonic acid by cyclooxygenases (COX) and prostaglandin synthases. The inducible COX-2 and the downstream microsomal prostaglandin E synthase-1 (mPGES-1) are overexpressed in a wide range of tumors, including high-grade brain tumors, and most reports show correlations with poor prognosis, although adverse results are reported. 6-8 PGE 2 has been alleged to exert immunosuppression by either direct effects on T cells by stimulating T h 2 cytokines as interleukin-10 (IL-10) and simultaneously inhibiting T h 1 cytokines as interferon-g (IFN-g) or by indirect effects via promotion of myeloid-derived suppressor cells (MDSCs) and regulatory T (T reg ) cells, which in turn induce T cell tolerance. [9][10][11][12] We and others have shown that peripheral immunotherapy using granulocyte macrophage-colony stimu...

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“…High levels of constitutive expression of COX-2 and its major product, PGE 2 , have been detected in various tumors, including CRC (Wang and DuBois, 2010a). PGE 2 is involved in tumor progression by inducing angiogenesis, invasion and metastasis in several solid tumors (Wang and DuBois, 2010b). Moreover, pharmacological, cell biological and gene targeting studies investigating COX-2 have demonstrated that PGE 2 produced through the COX-2-dependent pathway contributes to the progression of several types of cancer (Tsujii and DuBois, 1995;Tsujii et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

et al. 2011

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Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E 2 is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE 2 -biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of b-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D 2 and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MUs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MUs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MUs failed to facilitate tumor growth. The adoptive transfer of WT BM-MUs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MUs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

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Eicosanoids and cancer

Cited by 1,518 publications

References 139 publications

Prostaglandins antagonistically control Bax activation during apoptosis

Prostaglandins antagonistically control Bax activation during apoptosis

Intratumoral COX‐2 inhibition enhances GM‐CSF immunotherapy against established mouse GL261 brain tumors

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

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