Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

Ellerhorst, Julie A.; Ekmekçioğlu, Sühendan; Johnson, Marilyn K.; Cooke, Carolyn P.; Grimm, Elizabeth A.

doi:10.1038/sj.onc.1209419

Cited by 41 publications

(25 citation statements)

References 28 publications

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“…Lim et al showed that the PI3K-Akt pathway phosphorylates and activates eNOS, resulting in the activity of H-Ras and NRas and tumor growth (36). In addition, other previous studies reported NO-induced cell proliferation and cell invasion (38,39). The authors of these reports argue that NO-induced activation of Erk-1/2 leads to cell survival, in opposition to our data indicating the tumoricidal effects of NO.…”

Section: Discussioncontrasting

confidence: 56%

Nitric Oxide Inhibits the Proliferation and Invasion of Pancreatic Cancer Cells through Degradation of Insulin Receptor Substrate-1 Protein

Sugita

Kaneki

Furuhashi³

et al. 2010

Molecular Cancer Research

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Nitric oxide (NO), which plays a role in the posttranslational modification of proteins, exhibits tumoricidal activity. However, the mechanism remains largely unclear. We investigated whether the regulation of insulin receptor substrate (IRS)-1 protein expression and insulin/insulin-like growth factor (IGF) signaling by NO is involved in the proliferation and invasion of pancreatic cancer cells. NO donor inhibited insulin/IGF-I-stimulated phosphorylation of insulin receptor/IGF-I receptor, IRS-1, Akt/PKB, and glycogen synthase kinase-3β along with decreased expression of IRS-1 protein in MIAPaCa-2 cells, whereas NO donor enhanced the phosphorylation of extracellular signal-regulated kinase-1/2. In contrast, a selective inducible nitric oxide synthase inhibitor, 1400W, upregulated the expression of IRS-1 protein and the phosphorylation of IRS-1, Akt/PKB, and glycogen synthase kinase-3β, along with enhanced proliferation and invasion of Panc-1 cells expressing inducible nitric oxide synthase protein. NO donor induced IRS-1 protein reduction through increased ubiquitination and degradation. For the detection of the site responsible for NO-induced ubiquitination, IRS-1 deletion mutant genes were transfected and overexpressed in MIAPaCa-2 cells. The results indicate that the COOH terminus of the IRS-1 protein is required for NO donor-induced ubiquitination and protein degradation. Cells stably transfected with COOHterminal deletion mutants of IRS-1 exhibited reduced IGF signaling and cell proliferation compared with vector alone-transfected cells, with no influence of NO on IGF signaling and invasion, although stable transfectants with full-length IRS-1 protein exhibited remarkable NO-induced reduction in IGF signaling, cell proliferation, and invasion. These findings indicate that NO inhibits the proliferation and invasion of pancreatic cancer cells, at least in part, through upregulation of IRS-1 protein degradation and resultant downregulation of the insulin/ IGF-I-Akt pathway.

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Section: Discussioncontrasting

confidence: 56%

Nitric Oxide Inhibits the Proliferation and Invasion of Pancreatic Cancer Cells through Degradation of Insulin Receptor Substrate-1 Protein

Sugita

Kaneki

Furuhashi³

et al. 2010

Molecular Cancer Research

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“…Our results show increased Akt phosphorylation at Ser 473 in the hearts of obese female rats, which further support the hypothesis that Akt regulates NFκB activity and thereby iNOS expression. Moreover, the role of ERK1/2 in iNOS activation has been demonstrated and increased ERK1/2 phosphorylation usually upregulates both NFκB activity and iNOS protein expression [46,49,[61][62][63]. However, in the present study there were no differences in ERK1/2 phosphorylation between obese and control female rats.…”

Section: Interestingly Mariappan Et Al Reported Increased Nfκb Exprcontrasting

confidence: 54%

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Jovanović

Sudar-Milovanović

Obradović

et al. 2017

CVP

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Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular (CV) disease. Several studies have reported that oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression. In the present study, female Wistar rats were fed a standard diet or a HF diet (balanced diet for laboratory rats enriched with 42% fat) for 10 weeks. Gene and protein expression of iNOS were measured in heart tissue. HF diet-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<0.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF diet-fed rats. Expression of the p50 subunit of nuclear factor-κB (NFκB-p50) in heart lysate was increased by 77% (p<0.01) in HF diet-fed rats.Expression and phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2) in control and HF diet-fed rats were also examined. Expression of Akt and ERK1/2 were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho-ERK1/2/total ERK1/2/ in HF-fed rats.Estrogen receptor-α levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were examined and shown to be significantly reduced in HF diet-fed rats. Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFκB-p50 proteins. Decreased levels of oestradiol and ERα protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression.Key words: cardioprotection, cardiovascular disease, oestradiol, inducible nitric oxide synthase, obesity Abbreviations: Akt, protein kinase B; CD36, cluster of differentiation 36; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; DMT2, diabetes mellitus type 2; ERα, oestrogen receptor-α; ERs, oestrogen receptors; ERK1/2, extracellular signalregulated kinases 1/2; FFA, free fatty acids; HF, high fat; HOMA-IR, HOMA-index of insulin resistance; HOMA-β, HOMA-index of β-cell function; IκB, inhibitor of NFκB; iNOS, inducible nitric oxide synthase; IR, insulin resistance; NFκB-p50, the p50 subunit of nuclear factor-κB; TES, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid; TG, triglycerides VSMCs, vascular smooth muscle cells.

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“…Cells in OptiMEM media were transfected with 200 nmol/L Mcl-1 -specific or Bcl-2 -specific siRNA or Negative Control siRNA using Oligofectamine reagent (Invitrogen) according to manufacturer's transfection protocols and to ref. (85). After 5 h, 1 mL of growth media was added to the transfection media, and 24 h later, the media was completely replaced by growth media.…”

Section: Rna Interferencementioning

confidence: 99%

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

Chetoui

Sylla

Gagnon-Houde

et al. 2008

Molecular Cancer Research

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Resistance of malignant melanoma cells to Fas-mediated apoptosis is among the mechanisms by which they escape immune surveillance. However, the mechanisms contributing to their resistance are not completely understood, and it is still unclear whether antiapoptotic Bcl-2 -related family proteins play a role in this resistance. In this study, we report that treatment of Fas-resistant melanoma cell lines with cycloheximide, a general inhibitor of de novo protein synthesis, sensitizes them to anti-Fas monoclonal antibody (mAb) -induced apoptosis. The cycloheximide-induced sensitization to Fas-induced apoptosis is associated with a rapid down-regulation of Mcl-1 protein levels, but not that of Bcl-2 or Bcl-xL. Targeting Mcl-1 in these melanoma cell lines with specific small interfering RNA was sufficient to sensitize them to both anti-Fas mAb-induced apoptosis and activation of caspase-9.

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Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

Cited by 41 publications

References 28 publications

Nitric Oxide Inhibits the Proliferation and Invasion of Pancreatic Cancer Cells through Degradation of Insulin Receptor Substrate-1 Protein

Nitric Oxide Inhibits the Proliferation and Invasion of Pancreatic Cancer Cells through Degradation of Insulin Receptor Substrate-1 Protein

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

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