Unknown,Transcriptomics,Genomics,Proteomics

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Adaptaquin is an inhibitor of oxygen-sensing prolyl-hydroxylase domain enzymes that abrogates ATF4-dependent death and improves outcomes from brain hemorrhage

ABSTRACT: Disability or death secondary to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron and generation of oxidative stress. Iron chelators bind free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms remain unclear. Here we show that the hypoxia-inducible factor prolylhydroxylase (HIF PHD) family of iron-dependent oxygen sensors is an effector of iron chelation in abrogating ICH-induced death. Molecular reduction of the three HIF PHD isoforms in mouse striatum improves functional recovery following ICH. A low molecular weight, hydroxyquinoline inhibitor of the HIF PHDs, which we call adaptaquin, reduces neuronal death and behavioral deficits following ICH in distinct rodent models. Unexpectedly, adaptaquin protects from oxidative death by suppressing ATF4- dependent prodeath gene expression rather than by activating a HIF-dependent prosurvival pathway. Adaptaquin treated neurons

ORGANISM(S): Mus musculus

SUBMITTER: Giovanni Coppola

PROVIDER: E-GEOD-75048 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: The incidence of human papillomavirus (HPV) associated oropharyngeal carcinomas has increased rapidly over the last thirty years. These tumours behave as a distinct biological entity when compared to classical smoking- and alcohol-related disease. To gain more information regarding the pathway through pre-malignancy in HPV positive/HPV negative oropharyngeal carcinoma (OSCC), we investigated genomewide expression profiles in histopathologically confirmed tumour samples with site-matched normal epithelial controls. Methods: Twenty-four patients with primary oropharyngeal squamous cell carcinoma (4 with stage III and 20 with stage IV disease) were included in this prospective clinical trial (UKCRN11945). The tumour tissues were each assessed by a histopathologist with HPV status and typing by p16INK4A, consensus PGMY PCR, type-specific HPV16 DNA & RNA PCR and DNA sequencing. Fresh tissue samples were subjected to whole transcriptome analysis using the Illumina Bead Array (~47,000 transcripts) and the results validated with quantitative Real Time-PCR (qRT-PCR). In a separate cohort of twelve OSCC patients, laser capture micro-dissection of formalin fixed paraffin embedded (FFPE) tissue allowed RNA extraction from regions of in situ malignant change (with matched normal and invasive SCC samples). Results: The majority of OSCC patients (28/36) displayed evidence of high risk HPV positivity. Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established in HPV16 associated oropharyngeal cancer. These were involved in cell differentiation, proliferation and invasion and demonstrated considerable overlap with expression analysis data in other oncogenic pathways (SFRP1/CRCT1/DLG2/SYCP2/CRNN). SYCP2 showed the highest consistent fold change from baseline in both fresh frozen and FFPE tissue (qRT-PCR fresh frozen tissue [P<0.04]; FFPE tissue pre-invasive [P<0.01]; FFPE tissue invasive [P<0.01]), and aberrant expression of this meiosis-specific protein may contribute to genetic instability during HPV-associated cancer development. Conclusion: Investigation of differentially expressed genes in HPV-positive tumours may reveal unique pathways that can explain their different natural history and biological properties. The data from this study reveal SYCP2 (amongst others) as a potential biomarker in HPV positive oropharyngeal carcinoma, and if corroborated on a larger scale, may facilitate the development of a non-invasive screening tool. Twenty four samples (12 matched invasive oropharyngeal carcinoma and normal epithelial controls).

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Adaptaquin is an inhibitor of oxygen-sensing prolyl-hydroxylase domain enzymes that abrogates ATF4-dependent death and improves outcomes from brain hemorrhage

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