Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

Ibiza, Sales; Pérez-Rodríguez, Andrea; Ortega, Ángel; Martínez‐Ruiz, Antonio; Barreiro, Olga; García-Domínguez, Carlota A.; Víctor, Víctor M.; Esplugues, Juan V.; Rojas, José M.; Sánchez-Madrid, Francisco; Serrador, Juan Manuel

doi:10.1073/pnas.0711062105

Cited by 71 publications

(64 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we showed that the phosphorylation of ERK1/2 is upregulated by NO donor without the stimulating of growth factors in MIAPaCa-2 and HCT-116 cells. These results are in accordance with previous studies reporting that NO directly modifies H-Ras and N-Ras through S-nitrosylation, resulting in the activation of their signaling (22,42). The present study showed that U0126 completely inhibits phosphorylation of ERK1/2, although U0126 upregulates IGF-I-and EGF-stimulated Akt phosphorylation ( Figs.…”

Section: Discussionsupporting

confidence: 83%

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

Furuhashi

Sugita

Horino³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

Abstract.Nitric oxide (NO) shows tumoricidal activity. We had previously reported that NO downregulates the phosphatidylinositol-3-kinase/Akt pathway, but upregulates the MEK/ERK pathway downstream of growth factor signaling. We hypothesized that NO donor and MEK inhibitor in combination synergistically inhibit the viability of cancer cells compared to either NO donor or MEK inhibitor alone. We determined the effects of S-nitrosoglutathione (GSNO, NO-donor) and U0126 (MEK inhibitor) on insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) signaling, proliferation and invasion in cancer cell lines. GSNO inhibits phosphorylation of IGF-I receptor (IGF-IR), EGF receptor (EGFR) and Akt, but upregulates ERK1/2 phosphorylation in MIAPaCa-2 and HCT-116 cells after stimulation by IGF-I and EGF. On the other hand, U0126 inhibits phosphorylation of ERK1/2, but upregulates phosphorylation of IGF-IR and EGFR in MIAPaCa-2 and HCT-116 cells. The combination of GSNO and U0126 downregulates phosphorylation of IGF-IR, EGFR, Akt and ERK1/2 after stimulation by IGF-I and EGF. GSNO as well as U0126, inhibits the proliferation of MIAPaCa-2, HCT-116, Panc-1, MCF-7, HT-29 and AGS cells in a dose-dependent manner. GSNO and U0126 in combination synergistically inhibit proliferation and invasion of cancer cells. These results indicate that the combined treatment of NO donor and MEK inhibitor may be promising in cancer therapy.

show abstract

Section: Discussionsupporting

confidence: 83%

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

Furuhashi

Sugita

Horino³

et al. 2011

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…The regulation of rat sarcoma/extracellular signal-regulated kinase1 (Ras/ERK) signaling in antigen-stimulated T cells is compartmentalized by the local production of NO. eNOS positively regulates Ras activation during antigen-specific T cell-APC interactions by S-nitrosylation on the Golgi, thus favoring activation-induced T cell death (Ibiza et al, 2008). In human lung carcinoma cells, Caveolin (Cav)-1, a 21-24 KDa structural protein component of plasma membrane microdomains, termed caveolae, has been shown to function in vesicular trafficking, signal transduction, and cancer progression (Galbiati et al, 2001).…”

Section: No Functions In Immunity and Neurodegenerative Diseasementioning

confidence: 99%

Nitric oxide: promoter or suppressor of programmed cell death?

et al. 2010

View full text Add to dashboard Cite

Nitric oxide (NO) is a short-lived gaseous free radical that predominantly functions as a messenger and effector molecule. It affects a variety of physiological processes, including programmed cell death (PCD) through cyclic guanosine monophosphate (cGMP)-dependent andindependent pathways. In this field, dominant discoveries are the diverse apoptosis networks in mammalian cells, which involve signals primarily via death receptors (extrinsic pathway) or the mitochondria (intrinsic pathway) that recruit caspases as effector molecules. In plants, PCD shares some similarities with animal cells, but NO is involved in PCD induction via interacting with pathways of phytohormones. NO has both promoting and suppressing effects on cell death, depending on a variety of factors, such as cell type, cellular redox status, and the flux and dose of local NO. In this article, we focus on how NO regulates the apoptotic signal cascade through protein S-nitrosylation and review the recent progress on mechanisms of PCD in both mammalian and plant cells.

show abstract

“…4,12 The three Ras isoforms (H, K, and N-Ras) are small GTPases that convert the inactive GDP-bound Ras to the active GTP-bound form by recruiting Raf-1 or PI3K to the plasma membrane to activate several key downstream effectors, principally Akt. 36 -38 By phosphorylating eNOS, Akt augments NO synthesis that in turn, is hypothesized to promote S-nitrosylation of cysteines of Ras proteins, 12,13 as also occurs during activation of eNOStransfected T lymphocytes. 13 That reciprocally drives the PI3K/Akt pathway to maintain growth of tumors 12 and concomitant angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…36 -38 By phosphorylating eNOS, Akt augments NO synthesis that in turn, is hypothesized to promote S-nitrosylation of cysteines of Ras proteins, 12,13 as also occurs during activation of eNOStransfected T lymphocytes. 13 That reciprocally drives the PI3K/Akt pathway to maintain growth of tumors 12 and concomitant angiogenesis. 39,40 Moreover, deletion of p85␣, a regulatory subunit of PI3K, in mice has led to partially decreased GTPCH expression and BH4 synthesis activity, with subsequently attenuated NO production from iNOS in macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…The group of these small GTPases converts the inactive GDP-bound Ras to the active GTPbound that in turn, up-regulates PI3K/Akt and eNOS to maintain NO production. Although the formation of this positive feedback loop plays a crucial role in promoting tumor progression and T lymphocyte activation, 12,13 its role in regulating endothelial cells for angiogenesis is still not explored.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Roles of Tetrahydrobiopterin in Promoting Tumor Angiogenesis

Chen

Zeng

Wang

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Nitric oxide (NO), which is derived from endothelial NO synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an absolute requirement for eNOS activity. In this study, we investigated whether this activation is both maintained by a wild-type Ras/ phosphatidylinositol 3-kinase (PI3K)/Akt-positive feedback loop in endothelial cells and affects tumor angiogenesis. We found that supplementation of BH4 (via the pterin salvage pathway with Sep) increased Akt/eNOS phosphorylation in both human eNOS-transfected COS-7 cells and endothelial cells concomitant with increases in NO production, cell proliferation, migration, and tube formation. This augmentation was abrogated by a PI3K inhibitor. Sepiapterin (Sep) also increased GTP-bound wild-type Ras and PI3K/Akt/ eNOS activation, which was prevented by the eNOS inhibitor, N-Nitro-L-arginine methyl ester (L-NAME). Growth of new blood vessels from pre-existing ones, ensuring oxygen and nutrient supplies, is a crucial step in tumor cell proliferation, growth, and metastasis. This pathological angiogenesis is maintained by overproduction of proangiogenic factors, which act via a variety of signaling pathways in tumor stroma.1 Recent evidence suggests that nitric oxide (NO) provides crucial signals for angiogenesis in the tumor microenvironment, where moderate levels of NO are proangiogenic, 2,3 chiefly increasing DNA synthesis, cell proliferation and migration of endothelial cells to promote tumor angiogenesis. 4NO is a gaseous free radical, resulting from the conversion of L-arginine to citrulline by three distinct forms of NO synthase (NOS): endothelial NOS (eNOS), inducible NOS, and neuronal NOS in different cell types and tissues.5 eNOS is the principal isoform in tumor vascular endothelial cells. Under pathological conditions, eNOSderived NO is the dominant stimulus to angiogenesis in B16 melanomas.6 Inhibition of basal eNOS by caveolin-1, a protein that sequesters eNOS in caveolae, attenuates NO-dependent blood flow in tumors and delays their growth as xenografts.7 Similarly, tumor growth is enhanced in caveolin-1-deficient mice because of increased microvascular permeability and angiogenesis. 8 Inhibiting eNOS with L-arginine analogs (N-Nitro-L-arginine methyl ester [L-NAME], NG-Methyl-L-arginine [L-NMMA] and N-Nitro-L-arginine [L-NNA]) decreases both tumor blood flow and microvascular permeability in breast cancer xenografts.

show abstract

Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

Cited by 71 publications

References 34 publications

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

NO donor and MEK inhibitor synergistically inhibit proliferation and invasion of cancer cells

Nitric oxide: promoter or suppressor of programmed cell death?

Roles of Tetrahydrobiopterin in Promoting Tumor Angiogenesis

Contact Info

Product

Resources

About