Circulating Uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel
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ABSTRACT:
PROVIDER: PRJNA561615 | ENA |
REPOSITORIES: ENA
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Project description:High serum concentrations of kidney-derived protein uromodulin (Tamm-Horsfall protein or THP) have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI, and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with post-surgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the TRPM2 channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model, mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity and our findings might help to explain how circulating THP deficiency is linked with poor outcomes and increased mortality.
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Project description:Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAktSer473 and pERKThr202/Tyr204, which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells highly expressing TRPM2 through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing the rationale for TRPM2 inhibition in anti-neoplastic therapy.
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2014-09-01 | E-GEOD-40687 | biostudies-arrayexpress
Project description:There is overwhelming evidence indicating that human cancer is a genetic disease caused by sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, it is also increasingly apparent that cancer depends not only on mutations in these coding genes, but also on alterations in the large class of the non-coding RNAs (ncRNAs). Here, we report that one such long ncRNA, TRPM2-AS, an antisense transcript in respect to TRPM2, a gene encoding for a ion channel activated by oxidative stress, is significantly overexpressed in prostate cancer. High expression levels of either TRPM2-AS or of a related gene signature are linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Moreover, TRPM2-AS knock-out leads to apoptosis of prostate cancer cells, with transcriptional profiling indicating an unbearable increase of cellular stress in dying cells, coupled to the down-regulation of several already known oncological targets. Considering that TRPM2-AS transcripts are barely detectable in healthy cells, these data strongly suggest that it, beside being a novel prognostic marker, is also a suitable therapeutic target in prostate cancer and establish a strong rationale for developing agents targeting either its expression or the expression of molecules in its pathway.
2014-09-01 | GSE40687 | GEO
Project description:The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
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Project description:Next-generation sequencing (NGS) has revolutionized systems-based analysis of gene expression. The goals of this study are to compare the different transcripts between TRPM2 knockdown and control in the neural progenitor cells when the maternal hyperthermia was induced.
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