@article{CencettiBrunoBernacchionietal.2020, author = {Cencetti, Francesca and Bruno, Gennaro and Bernacchioni, Caterina and Japtok, Lukasz and Puliti, Elisa and Donati, Chiara and Bruni, Paola}, title = {Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P(2) receptor axis}, series = {Biochimica et biophysica acta : Molecular and cell biology of lipids}, volume = {1865}, journal = {Biochimica et biophysica acta : Molecular and cell biology of lipids}, number = {9}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1388-1981}, doi = {10.1016/j.bbalip.2020.158759}, pages = {9}, year = {2020}, abstract = {The bioactive sphingolipid sphingosine 1-phosphate (S1P) has emerged in the last three decades as main regulator of key cellular processes including cell proliferation, survival, migration and differentiation. A crucial role for this sphingolipid has been recognized in skeletal muscle cell biology both in vitro and in vivo. S1P lyase (SPL) is responsible for the irreversible degradation of S1P and together with sphingosine kinases, the S1P producing enzymes, regulates cellular S1P levels. In this study is clearly showed that the blockade of SPL by pharmacological or RNA interference approaches induces myogenic differentiation of C2C12 myoblasts. Moreover, down-regulation of the specific S1P transporter spinster homolog 2 (Spns2) abrogates myogenic differentiation brought about by SPL inhibition or down-regulation, pointing at a role of extracellular S1P in the pro-myogenic action induced by SPL blockade. Furthermore, also S1P(2) receptor down-regulation was found to abrogate the pro-myogenic effect of SPL blockade. These results provide further proof that inside-out S1P signaling is critically implicated in skeletal muscle biology and provide support to the concept that the specific targeting of SPL could represent an exploitable strategy to treat skeletal muscle disorders.}, language = {en} } @article{BernacchioniGhiniCencettietal.2017, author = {Bernacchioni, Caterina and Ghini, Veronica and Cencetti, Francesca and Japtok, Lukasz and Donati, Chiara and Bruni, Paola and Turano, Paola}, title = {NMR metabolomics highlights sphingosine kinase-1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells}, series = {Molecular oncology / Federation of European Biochemical Societies}, volume = {11}, journal = {Molecular oncology / Federation of European Biochemical Societies}, publisher = {Wiley}, address = {Hoboken}, issn = {1878-0261}, doi = {10.1002/1878-0261.12048}, pages = {517 -- 533}, year = {2017}, abstract = {Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.}, language = {en} } @article{LaurenzanaCencettiSerratietal.2015, author = {Laurenzana, Anna and Cencetti, Francesca and Serrati, Simona and Bruno, Gennaro and Japtok, Lukasz and Bianchini, Francesca and Torre, Eugenio and Fibbi, Gabriella and Del Rosso, Mario and Bruni, Paola and Donati, Chiara}, title = {Endothelial sphingosine kinase/SPNS2 axis is critical for vessel-like formation by human mesoangioblasts}, series = {Journal of molecular medicine}, volume = {93}, journal = {Journal of molecular medicine}, number = {10}, publisher = {Springer}, address = {New York}, issn = {0946-2716}, doi = {10.1007/s00109-015-1292-0}, pages = {1145 -- 1157}, year = {2015}, abstract = {The interaction between endothelial cells and pericytes is crucial for the stabilization of newly formed vessels in angiogenesis. The comprehension of the mechanisms regulating peiicyte recruitment might open therapeutical perspectives on vascular-related pathologies. Sphingosine 1phosphate (SIP) is a bioactive sphingolipid that derives from sphingomyelin catabolism and regulates biological functions in cell survival, proliferation, and differentiation. In this study, we aimed to identify the role of SIP axis in the intercellular communication between human mesenchymal progenitor mesoangioblasts (MAB) and endothelial cells (human microvascular endothelial cells (HMVEC)) in the formation of capillary-like structures. We demonstrated that the SIP biosynthetic pathway brought about by sphingosine kinases (SK) SKI and SK2 as well as spinster homolog 2 (SPNS2) transporter in H-MVEC is crucial for MAB migration measured by Boyden chambers and for the formation and stabilization of capillary-like structures in a 3D Matrigel culture. Moreover, the conditioned medium (CM) harvested from HMVEC, where SKI, 5K2, and SPNS2 were down-regulated, exerted a significantly diminished effect on MAB capillary morphogenesis and migration. Notably, we demonstrated that S I Pi and Si p3 receptors were positively involved in CM-induced capillary-like formation and migration, while S I P2 exerted a negative role on CM-induced migratory action of MAB. Finally, SK inhibition as well as MAB SlPi and S1P3 down-regulation impaired HMVEC-MAB cross-talk significantly reducing in vivo angiogenesis evaluated by Matrigel plug assay. These findings individuate novel targets for the employment of MAB in vascular-related pathologic conditions.}, language = {en} } @article{BrunoCencettiPerticietal.2015, author = {Bruno, Gennaro and Cencetti, Francesca and Pertici, Irene and Japtok, Lukasz and Bernacchioni, Caterina and Donati, Chiara and Bruni, Paola}, title = {CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P(3) signaling axis: Implications in the action mechanism of TGF beta}, series = {Biochimica et biophysica acta : Molecular and cell biology of lipids}, volume = {1851}, journal = {Biochimica et biophysica acta : Molecular and cell biology of lipids}, number = {2}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1388-1981}, doi = {10.1016/j.bbalip.2014.11.011}, pages = {194 -- 202}, year = {2015}, abstract = {The matricellular protein connective tissue growth factor (CTGF/CCN2) is recognized as key player in the onset of fibrosis in various tissues, including skeletal muscle. In many circumstances, CTGF has been shown to be induced by transforming growth factor beta (TGF beta) and accounting, at least in part, for its biological action. In this study it was verified that in cultured myoblasts CTGF/CCN2 causes their transdifferentiation into myofibroblasts by up-regulating the expression of fibrosis marker proteins alpha-smooth muscle actin and transgelin. Interestingly, it was also found that the profibrotic effect exerted by CTGF/CCN2 was mediated by the sphingosine kinase (SK)-1/S1P(3) signaling axis specifically induced by the treatment with the profibrotic cue. Following CTGF/CCN2-induced up-regulation, S1P(3) became the SIP receptor subtype expressed at the highest degree, at least at mRNA level, and was thus capable of readdressing the sphingosine 1-phosphate signaling towards fibrosis rather than myogenic differentiation. Another interesting finding is that CTGF/CCN2 silencing prevented the TGF beta-dependent up-regulation of SKI/S1P(3) signaling axis and strongly reduced the profibrotic effect exerted by TGF beta, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGF beta challenge in the transmission of at least part of its profibrotic effect These results provide new insights into the molecular mechanism by which CTGF/CCN2 drives its biological action and strengthen the concept that SK1/S1P(3) axis plays a critical role in the onset of fibrotic cell phenotype. (C) 2014 Elsevier B.V. All rights reserved.}, language = {en} }