Importance of PIKKs in NF-κB activation by genotoxic stress

Sabatel, Hélène; Pirlot, Céline; Piette, Jacques; Habraken, Yvette

doi:10.1016/j.bcp.2011.07.105

Cited by 35 publications

(31 citation statements)

References 167 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Phosphorylation of the p65 unit of NF-kappaB initiates its activation and plays an important role in regulating the specificity of the NF-kappaB-dependent gene expression [36]. Suramin may regulate expression of multiple cytokines and chemokines, through activation of NF-kappaB.…”

Section: Resultsmentioning

confidence: 99%

“…EGFR and PDGFR have been shown to mediate activation of all three signaling pathways described above [36], [39], and they play a central role in the activation and proliferation of renal fibroblasts leading to renal fibrogenesis in a variety of pathological settings [40], [41], [42], [43]. We examined the effect of suramin on the activation of these two receptors.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney

Liu

Tolbert

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

BackgroundRecently, we demonstrated that suramin, a compound that inhibits the interaction of multiple cytokines/growth factors with their receptors, inhibits activation and proliferation of renal interstitial fibroblasts, and attenuates the development of renal interstitial fibrosis in the murine model of unilateral ureteral obstruction (UUO). However, it remains unclear whether suramin can alleviate glomerular and vascular lesions, which are not typical pathological changes in the UUO model. So we tested the efficacy of suramin in the remnant kidney after 5/6 nephrectomy, a model characterized by the slow development of glomerulosclerosis, vascular sclerosis, tubulointerstitial fibrosis and renal inflammation, mimicking human disease.Methods/Findings5/6 of normal renal mass was surgically ablated in male rats. On the second week after surgery, rats were randomly divided into suramin treatment and non-treatment groups. Suramin was given at 10 mg/kg once per week for two weeks. In the remnant kidney of mice receiving suramin, glomerulosclerosis and vascular sclerosis as well as inflammation were ameliorated. Suramin also attenuated tubular expression of two chemokines, monocyte chemoattractant protein-1 and regulated upon expression normal T cell expressed and secreted (RANTES). After renal mass ablation, several intracellular molecules associated with renal fibrosis, including NF-kappaB p65, Smad-3, signal transducer and activator of transcription-3 and extracellular regulated kinase 1/2, are phosphorylated; suramin treatment inhibited their phosphorylation. Futhermore, suramin abolished renal ablation-induced phosphorylation of epidermal growth factor receptor and platelet derived growth factor receptor, two receptors that mediate renal fibrosis.Conclusions and SignificanceThese findings suggest that suramin attenuates glomerular and vascular injury and reduces inflammatory responses by suppression of multiple growth factor receptor-mediated profibrotic signaling pathways. Therefore, suramin may be a useful drug in preventing the fibrosis and sclerosis that characterizes progression of chronic kidney disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney

Liu

Tolbert

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…The immune infiltrate may, however, be in response to the immune signal originating from DDRD tumor cells. In support of this, there is increasing evidence that damaged DNA, as occurs spontaneously in FA/BRCA–deficient tumors, can activate immune pathways similar to viral infection (33). Indeed, it has recently been reported that expression of a collection of immune genes associates with response to anthracycline-based chemotherapy in publically available datasets (34).…”

Section: Discussionmentioning

confidence: 96%

Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer

Mulligan¹,

Hill²,

Deharo³

et al. 2014

JNCI: Journal of the National Cancer Institute

View full text Add to dashboard Cite

BackgroundThere is no method routinely used to predict response to anthracycline and cyclophosphamide–based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.MethodsDNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.ResultsIn a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.ConclusionsA formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide–based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.

show abstract

“…The phosphorylation of the p65 unit of NF-κB has been reported to initiate its activation and plays an important role in regulating the specificity of NF-κB-dependent gene expression (23). In this study, to investigate whether NF-κB activation is involved in the effects of oxidized HDL, the HK-2 cells were pre-incubated with various concentrations of oxidized HDL or HDL, as already mentioned in the previous sections.…”

Section: Oxidized Hdl Activates Nuclear Factor-κb (Nf-κb) Proteins Inmentioning

confidence: 94%

Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36

Gao

Qian

et al. 2014

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Abstract. Unlike native high-density lipoprotein (HDL), oxidized HDL exerts adverse effects in a number of diseases, including chronic kidney disease (CKD); however, the mechanisms involved in this process remain unclear. In the present study, we investigated the effects of oxidized HDL on renal tubular cells, which play an important role in the progression of CKD. Human renal proximal tubule epithelial cells (HK-2) were cultured and stimulated with various concentrations of oxidized HDL in the absence or presence of CD36 siRNA. The results revealed that oxidized HDL enhanced the production of reactive oxygen species (ROS) and upregulated the expression of pro-inflammatory factors in the HK-2 cells in a dose-dependent manner. Incubation with oxidized HDL also increased the apoptosis of the HK-2 cells and reduced their migration ability in a dose-dependent manner. Src family kinase, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were activated following stimulation with oxidized HDL. All these effects mediated by oxidized HDL on HK-2 cells were markedly attenuated by transfection with with CD36 siRNA pior to stimulation with oxidized HDL. These findings suggest that oxidized HDL enhances the pro-inflammatory properties and impairs the function of HK-2 cells, mainly through the scavenger receptor, CD36, as well as through the Src, MAPK and NF-κB pathways.

show abstract

Importance of PIKKs in NF-κB activation by genotoxic stress

Cited by 35 publications

References 167 publications

Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney

Suramin Alleviates Glomerular Injury and Inflammation in the Remnant Kidney

Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer

Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36

Contact Info

Product

Resources

About