Biology subjects

Raoul, W.

Publications and source records attributed to Raoul, W..

4 recordsLinked to original sources

bioRxiv2023

Encoding of the colorectal cancer metabolic program through MICU2

The mitochondrial Ca2+ uniporter (MCU) plays crucial role in intramitochondrial Ca2+ uptake, allowing Ca2+-dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and migration using in vitro and in vivo models of colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming. HighlightsO_LIMICU2 plays a pivotal role in the balance between anaerobic glycolysis and oxidative phosphorylation C_LIO_LIMICU2 stabilizes the mitochondrial network and endoplasmic reticulum-mitochondrial calcium flux C_LIO_LIMICU2 expression and the MICU2/MICU1 ratio control proliferation and metastasis formation in colorectal cancer C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/564893v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@6bb307org.highwire.dtl.DTLVardef@b6a966org.highwire.dtl.DTLVardef@2ba053org.highwire.dtl.DTLVardef@2ab691_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Curcumin and NCLX Inhibitors Share Anti-Tumoral Mechanisms in Microsatellite-Instability-Driven Colorectal Cancer

Colorectal cancer (CRC) is associated with high mortality worldwide and new targets are needed to overcome treatment resistance. Recent evidences highlight a role of the mitochondria calcium homeostasis in the development of CRC. In this context, we aimed to evaluate the role of the mitochondrial sodium-calcium-lithium exchanger (NCLX) and its targeting in CRC. We also identified curcumin as a new potential inhibitor of NCLX. In vitro, curcumin exerted strong anti-tumoral activity through its action on NCLX with mtCa2+ and reactive oxygen species overload associated with a mitochondrial membrane depolarization, leading to reduced ATP production and apoptosis through mitochondrial permeability transition pore opening concomitant with G2/M cell cycle arrest. NCLX inhibition with either CGP37157 (a benzodiazepine derivative), small interfering RNA-mediated knock-down or knockout approaches reproduced the effects of curcumin. Altered mitochondrial respiration, cellular aerobic glycolysis and endoplasmic reticulum-mitochondria membrane perturbations participated in these mechanisms. In a xenograft mouse model, NCLX inhibitors decreased CRC tumor growth. Both transcriptomic analysis of The Cancer Genome Atlas dataset and immunohistochemical analysis of tissue microarrays from 381 patients with microsatellite instability (MSI)-driven CRC demonstrated that higher NCLX expression was associated with MSI status and for the first time NCLX expression was significantly associated with recurrence-free survival in MSI CRC patients. Our findings provide strong evidence that blocking NCLX inhibits CRC in vitro and in vivo. We highlight a novel anti-tumoral mechanism of curcumin through its action on NCLX and mitochondria calcium overload that could benefit for therapeutic treatment of patients with MSI CRC.

cancer biology↗

bioRxiv2018

Evaluation of lung VEGF-A transduction during hyperoxia-induced injury in rats

BackgroundSince Vascular Endothelial Growth Factor (VEGF) is a main factor for endothelial survival, we evaluated whether VEGF transduction could ameliorate hyperoxia induced injury, which is associated with predominant endothelial injury.\n\nMethods and ResultsTransduction (induced 48 hours before hyperoxic exposure) using adenoviral vector (Ad.) for VEGF (1010 viral particles [VP]) increased moderately survival under hyperoxia (fraction of inspired oxygen [FIO2] >95%) as compared with Ad.Null (1010 VP) transduction, whereas VEGF transduction with a lower dose (5.109 VP) had no effect. After 48 hours of hyperoxia, Ad.VEGF transduction increased lung VEGF concentration, prevented the diffuse loss of capillary bed and induced patchy areas of endothelial cell proliferation (CD31 immunostaining) with interstitial inflammatory cell recruitment as compared to Ad. Null transduction. Hyperoxia was associated with diffuse apoptosis that was inhibited only in patchy areas of endothelial proliferation under VEGF transduction. Hyperoxia-induced alveolar inflammation was similar with Ad.Null and Ad.VEGF. Under normoxia, the high dose of VEGF transduction induced diffuse alveolar inflammation whereas the low dose did not suggesting a pro-inflammatory effect of VEGF that may have participated to increased survival under hyperoxia.\n\nConclusionsWe demonstrate that lung VEGF-A transduction despite inhibition of the loss of capillary bed has a marginal effect of on animal survival during hyperoxia-induced injury.

pathology↗

bioRxiv2018

Single-Dose Monocrotaline Pyrrole Injection as a Model of Pulmonary Endothelial Injury In Mice

Monocrotaline (MCT) is a plant substance that induces severe pulmonary hypertension in several animals except for mice. The aim of our study was to state whether monocrotaline pyrrole (MCTp), the main monocrotaline metabolite, could induce significant injury in mouse lung when given intravenously. MCTp caused moderate pulmonary inflammation, remodelling of small distal vessels (percentage of muscularized arteries: 33,5 vs 20,6%, p[≤]0,0006) and a right ventricular dysfunction (RVSP 27,8mmHg vs 16,4mmHg, p[≤]0,0001; Fulton index 0,35 vs 0,26, p[≤]0,0007). These vascular effects were associated with a decrease in eNOS protein expression in lung tissues and resolved after 45 days. In conclusion, we developed a model of endothelial dysfunction and transient pulmonary hypertension in mice.

physiology↗