The role of tumour-derived iNOS in tumour progression and angiogenesis

Kostourou, Vassiliki; Cartwright, Judith E.; Johnstone, Alan P.; Boult, Jessica K.R.; Cullis, Elizabeth R.; Whitley, Guy; Robinson, Simon P.

doi:10.1038/sj.bjc.6606034

Cited by 88 publications

(82 citation statements)

References 36 publications

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“…In addition to exploiting iNOS/NO for proliferative signaling, glioblastoma cells are known to rely on NO for migratory and invasive potency (26,(42)(43)(44). We compared the effects of 1400W and JQ1 on surviving U87 cell invasiveness after a typical ALA/light challenge.…”

Section: Jq1 Suppression Of Inos/no Anti-pdt Effectsmentioning

confidence: 99%

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

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Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion, and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells upregulate iNOS after a photodynamic challenge and that resulting NO not only increased resistance to apoptosis, but rendered surviving cells more proliferative and invasive. These findings were largely based on the effects of inhibiting iNOS activity and scavenging NO. Demonstrating now that iNOS expression in photostressed U87 cells is mediated by NF-κB, we hypothesized that (i) recognition of acetylated lysine (acK) on NF-κB p65/Rel A by bromodomain and extra-terminal (BET) protein Brd4 is crucial, and (ii) by suppressing iNOS expression, a BET inhibitor (JQ1) would attenuate the negative effects of photostress. The following evidence was obtained: (i) Like iNOS, Brd4 protein and p65-acK levels increased several fold in photostressed cells; (ii) JQ1 at minimally toxic concentrations had no effect on Brd4 or p65-acK upregulation after PDT, but strongly suppressed iNOS, survivin, and Bcl-xL upregulation, along with the growth and invasion spurt of PDTsurviving cells; (iii) JQ1 inhibition of NO production in photostressed cells closely paralleled that of growth/invasion inhibition; (iv) At 1% the concentration of iNOS inhibitor 1400W, JQ1 reduced post-PDT cell aggressiveness to a far greater extent. This is the first evidence for BET inhibitor targeting of iNOS expression in cancer cells and how such targeting can markedly improve therapeutic efficacy.

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Section: Jq1 Suppression Of Inos/no Anti-pdt Effectsmentioning

confidence: 99%

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

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“…Increased iNOS expression by MDSCs, and thus higher levels of NO, may also induce cell cycle arrest of T cells 83 and has been shown to be related to tumor progression and angiogenesis. 84 In addition, increased NO blocks T cell production of IL-2, 85,86 a cytokine that stimulates T-cell proliferation. Consequently, the use of inhibitors against arginase/iNOS, such as N(omega)-Hydroxy-nor-L-arginine (nor-NOHA), N(omega)-Hydroxy-L-arginine (NOHA), [87][88][89] or the iNOS inhibitor N GMonomethyl-L-arginine, monoacetate salt (L-NMMA), has been shown to restore T-cell expansion and block tumor growth in mouse models.…”

Section: Molecular Mechanisms Of Immune Evasion By Tumorsmentioning

confidence: 99%

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

et al. 2015

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“…Furthermore, increased nNOS expression has been observed in glial neoplasms. The highest nNOS values were observed in world health organization (WHO) grade III and IV tumors, and in carcinoma and melanoma metastasic tissues, whereas no or low nNOS expression was observed in WHO grade I or II tumors, and in meningiomas (20,21). iNOS expression is induced in different types of human brain tumors, including gliomas (22), where it is known to promote glioma stem cell proliferation and tumor growth (23).…”

Section: Effects Of Nitric Oxide Synthase Deficiency On a Disintegrinmentioning

confidence: 99%

“…NO activity has been extensively studied in tumor biology (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). It appears to be involved in all phases of carcinogenesis (12).…”

Section: Effects Of Nitric Oxide Synthase Deficiency On a Disintegrinmentioning

confidence: 99%

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples

Lendeckel¹,

Wolke²,

Bernstein

et al. 2015

Molecular Medicine Reports

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Abstract.A d isi nt eg r i n a nd met a l loprot ei nase domain-containing protein 12 (ADAM12) belongs to the ADAM family of transmembrane proteins. Via proteolysis, cell adhesion, cell-cell fusion, cell-matrix interaction and membrane protein shedding, ADAM proteins are involved in normal brain development, and also in cancer genesis and progression, and in inflammation. Therefore, neurobiological research focusing on this protein is increasing. Nitric oxide (NO), which is endogenously produced by NO synthases (NOS), is associated with glial tumors. However, knock-out of NOS produces only limited antitumor effects. The present study analyzed the expression of ADAM12 in the cortex and hippocampus of C57/BL6 wild-type mice, and endothelial NOS-, neuronal NOS-(nNOS) or inducible NOS (iNOS)-deficient ( -/-) mice, at different stages of development. Expression of ADAM12 was quantified using immunoblot analysis of cortical and hippocampal tissue samples from fetal, neonatal (5 days postnatal), adult (12 weeks old) or >1 year old mice. Using reverse transcription-quantitative polymerase chain reaction, ADAM12 expression was analyzed in cultured N9, OLN93, C6 and PC12 cells, representing the four main cell types in the brain, following NOS inhibition. ADAM12 expression was low in all mouse genotypes and regions of the brain, and in fetal and neonatal mice, an increase in expression was observed with increasing age. The highest levels of expression were observed in the cortex of adult mice, iNOS -/-mice of >1 year and wild-type mice, and in the hippocampus of adult and iNOS -/-mice of >1 year. By contrast, ADAM12 expression was lowest in adult nNOS -/-mice. Inhibition of NOS using N ω -Nitro-L-arginine methyl ester hydrochloride, induced ADAM12 mRNA expression in N9 and PC12 cell lines. Inhibition of NOS using L-N 6 -(1-Iminoethyl)lysine dihydrochloride, induced ADAM12 mRNA expression in N9 and C6 cell lines. No change in ADAM12 expression was observed in OLN93 cells following NOS inhibition. ADAM12 expression in mouse hippocampus and cortex samples demonstrated considerable variation during development, with a marked increase observed in adult and >1 year old mice, compared with that in fetal and neonatal mice. IntroductionNitric oxide (NO) is an important signaling molecule found in animals, including humans. Reduced NO production is associated with important cardiovascular risk factors, such as hyperlipidemia (1,2), diabetes, hypertension, smoking, atherosclerosis and aging (3). The bioavailability of NO in cells and tissues decreases with age. This may be a result of a decrease in the expression of the constitutive isoforms [endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS)], with age (4). Inducible NOS (iNOS)-mediated NO formation has been shown to affect longevity. In mice, iNOS overexpression may lead to increased mortality, which is associated with cardiac hypertrophy and sudden cardiac death as a result of bradyarrhythmias (5). iNOS expression is typically not observed in the brains of young (1-3...

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The role of tumour-derived iNOS in tumour progression and angiogenesis

Cited by 88 publications

References 36 publications

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

Effects of nitric oxide synthase deficiency on a disintegrin and metalloproteinase domain-containing protein 12 expression in mouse brain samples

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