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Castellana Grotte, Italy

Peserico A.,Laboratory of Signal dependent Transcription | Chiacchiera F.,Laboratory of Signal dependent Transcription | Grossi V.,Cancer Genetics Laboratory | Matrone A.,Laboratory of Signal dependent Transcription | And 11 more authors.
Cellular and Molecular Life Sciences | Year: 2013

Reduction of nutrient intake without malnutrition positively influences lifespan and healthspan from yeast to mice and exerts some beneficial effects also in humans. The AMPK-FoxO axis is one of the evolutionarily conserved nutrient-sensing pathways, and the FOXO3A locus is associated with human longevity. Interestingly, FoxO3A has been reported to be also a mitochondrial protein in mammalian cells and tissues. Here we report that glucose restriction triggers FoxO3A accumulation into mitochondria of fibroblasts and skeletal myotubes in an AMPK-dependent manner. A low-glucose regimen induces the formation of a protein complex containing FoxO3A, SIRT3, and mitochondrial RNA polymerase (mtRNAPol) at mitochondrial DNA-regulatory regions causing activation of the mitochondrial genome and a subsequent increase in mitochondrial respiration. Consistently, mitochondrial transcription increases in skeletal muscle of fasted mice, with a mitochondrial DNA-bound FoxO3A/SIRT3/mtRNAPol complex detectable also in vivo. Our results unveil a mitochondrial arm of the AMPK-FoxO3A axis acting as a recovery mechanism to sustain energy metabolism upon nutrient restriction. © 2012 Springer Basel.

Chang A.,Michael Smith Genome science Center | Fu Y.,Michael Smith Genome science Center | Garside V.,Terry Fox Laboratory | Niessen K.,Michael Smith Genome science Center | And 13 more authors.
Developmental Cell | Year: 2011

The heart is the most common site of congenital defects, and valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn. The process of endothelial-to-mesenchymal transition (EndMT) in the cardiac cushions is a required step during early valve development, and Notch signaling is required for this process. Here we show that Notch activation induces the transcription of both subunits of the soluble guanylyl cyclase (sGC) heterodimer, GUCY1A3 and GUCY1B3, which form the nitric oxide receptor. In parallel, Notch also promotes nitric oxide (NO) production by inducing Activin A, thereby activating a PI3-kinase/Akt pathway to phosphorylate eNOS. We thus show that the activation of sGC by NO through a Notch-dependent autocrine loop is necessary to drive early EndMT in the developing atrioventricular canal (AVC). © 2011 Elsevier Inc.

Germani A.,Laboratory of Signal dependent Transcription | Matrone A.,Laboratory of Signal dependent Transcription | Grossi V.,Cancer Genetics Laboratory | Peserico A.,Laboratory of Signal dependent Transcription | And 10 more authors.
Cancer Letters | Year: 2014

Chemoresistance is a major obstacle to effective therapy against colorectal cancer (CRC) and may lead to deadly consequences. The metabolism of CRC cells depends highly on the p38 MAPK pathway, whose involvement in maintaining a chemoresistant behavior is currently being investigated. Our previous studies revealed that p38α is the main p38 isoform in CRC cells. Here we show that p38α pharmacological inhibition combined with cisplatin administration decreases colony formation and viability of cancer cells and strongly increases Bax-dependent apoptotic cell death by activating the tumor suppressor protein FoxO3A. Our results indicate that FoxO3A activation up-regulates transcription of its target genes (p21, PTEN, Bim and GADD45), which forces both chemosensitive and chemoresistant CRC cells to undergo apoptosis. Additionally, we found that FoxO3A is required for apoptotic cell death induction, as confirmed by RNA interference experiments. In animal models xenografted with chemoresistant HT29 cells, we further confirmed that the p38-targeted dual therapy strategy produced an increase in apoptosis in cancer tissue leading to tumor regression. Our study uncovers a major role for the p38-FoxO3A axis in chemoresistance, thereby suggesting a new therapeutic approach for CRC treatment; moreover, our results indicate that Bax status may be used as a predictive biomarker. © 2013 Elsevier Ireland Ltd.

Grimwade D.,Kings College London | Grimwade D.,Cancer Genetics Laboratory
Best Practice and Research: Clinical Haematology | Year: 2012

Acute myeloid leukaemia (AML) is a highly heterogeneous disease, with biologically and prognostically different subtypes distinguished by cytogenetic and molecular genetic analysis, as recognised in the latest (2008) WHO classification system. However, since the publication of this schema, application of various high throughout technologies including whole genome and exome sequencing of AML cases has revealed a plethora of recurrent mutational targets, including a number of genes encoding transcriptional regulators, not previously implicated in leukaemogenesis. Deciphering the combinations of mutations that cooperate to induce AML and determining which particular alterations (or combinations) confer independent prognostic information represent major ongoing challenges, which will necessitate analysis of large cohort sizes involving international cooperation. However, the uncertainty concerning optimal risk-stratification of AML based on the rapidly evolving picture emerging from molecular genetic profiling provides a strong rationale for evaluation of minimal residual disease (MRD) detection as a tool to refine outcome prediction. This modality may not only capture differences in treatment response that reflect the underlying molecular heterogeneity, but also inter-patient variability in drug availability and metabolism, which may also significantly influence outcome. Developments in leukaemia diagnostics coupled with the possibility that MRD may be tracked using molecular and/or flow cytometry-based methods in the majority of patients hold considerable promise to inform more personalised approaches to therapy. © 2012 Elsevier Ltd. All rights reserved.

Grossi V.,Cancer Genetics Laboratory | Liuzzi M.,University of Bari | Murzilli S.,Laboratory of Lipid Metabolism and Cancer | Martelli N.,Laboratory of Lipid Metabolism and Cancer | And 5 more authors.
Cancer Biology and Therapy | Year: 2012

In the search for new strategies to efficiently fight colorectal cancer, efforts are being increasingly focused on targeting regulatory signaling pathways involved in cancer-specific features. As a result, several studies have recently addressed the therapeutic potential of molecularly-targeted drugs capable of inhibiting the activity of protein kinases involved in relevant signaling cascades. Here we show that simultaneous inhibition of the DFG-in and DFG-out conformations of p38α by means of type-I and type-II inhibitors is beneficial to impair more efficiently its kinase activity. Moreover, we found that SB202190 (type-I) and sorafenib (type-II) synergize at the molecular and biological level, as co-treatment with these compounds enhances tumor growth inhibition and induction of apoptosis both in colorectal cancer cell lines and animal models. These results support the need to reconsider sorafenib as a therapeutic agent against colorectal cancer and provide new insights that underline the importance to elucidate the activity of protein kinase inhibitors for the treatment of colorectal carcinoma. © 2012 Landes Bioscience.

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