Elena Sacco

Elena Sacco
Università degli Studi di Milano-Bicocca | UNIMIB · Department of Biotechnology and Biosciences

PhD
Characterization and targeting of metabolism, redox homeostasis and Ras signaling in 2D and 3D cancer cellular models

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50
Publications
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562
Citations

Publications

Publications (50)
Article
Full-text available
Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has been discussed for its safety and efficacy in cancer treatments. For this reason, we have inquired into its use on triple-negative human breast cancer. Analyzing the biological effects of CBD on MDA-MB-231, we have demonstrated that both CBD dosage and serum concentrations in the cul...
Article
Bladder cancer (BC) is one of the most common malignancies worldwide[1]. Most patients are diagnosed with non-muscle invasive BC, which is associated with frequent recurrence. The prognosis for early-stage bladder tumors is generally good; however, patients often progress to invasive disease resulting in a much less favorable outcome[2,3]. 3D cultu...
Article
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Background Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34 ⁺ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (C...
Article
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Three-dimensional cancer models, such as spheroids, are increasingly being used to study cancer metabolism because they can better recapitulate the molecular and physiological aspects of the tumor architecture than conventional monolayer cultures. Although Agilent Seahorse XFe96 (Agilent Technologies, Santa Clara, CA, United States) is a valuable t...
Article
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RalGPS2 is a Ras-independent Guanine Nucleotide Exchange Factor for RalA GTPase that is involved in several cellular processes, including cytoskeletal organization. Previously, we demonstrated that RalGPS2 also plays a role in the formation of tunneling nanotubes (TNTs) in bladder cancer 5637 cells. In particular, TNTs are a novel mechanism of cell...
Article
Full-text available
Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4-previously identified as a water-soluble Ras inhibitor-targets multiple steps in the activation and downstrea...
Article
Background and Aims Little is known about the metabolic regulation of cancer stem cells (CSC) in cholangiocarcinoma (CCA). We analyzed whether mitochondrial-dependent metabolism and related signaling pathways contribute to stem state in CCA. Methods The stem-like subset was enriched by sphere culture (SPH) in human intrahepatic CCA cells (HUCCT1 a...
Article
Full-text available
Bladder cancer is one of the most prevalent deadly diseases worldwide. Grade 2 tumors represent a good window of therapeutic intervention, whose optimization requires high resolution biomarker identification. Here we characterize energy metabolism and cellular properties associated with spreading and tumor progression of RT112 and 5637, two Grade 2...
Article
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RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in RAS genes...
Article
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Metabolomics is a rapidly expanding technology that finds increasing application in a variety of fields, form metabolic disorders to cancer, from nutrition and wellness to design and optimization of cell factories. The integration of metabolic snapshots with metabolic fluxes, physiological readouts, metabolic models, and knowledge-informed Artifici...
Chapter
Many high-throughput post-genomics (-omics) technologies have been developed to unravel cellular complexity and to investigate biological systems. Each -omics technology (such as genomics, transcriptomics, proteomics, or metabolomics) deals with a different layer of cellular or tissue functioning. The integration of two or more -omics connects thes...
Article
Recent epidemiological studies demonstrate that consumption of healthy foods, especially rich in polyphenols content, might reduce the incidence of cancer and degenerative diseases. In particular, chlorogenic acids (CGAs) occur ubiquitously in food, representing the most abundant polyphenols in the human diet. A number of CGA beneficial biological...
Article
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Background: Cancer cells have an increased demand for amino acids and require transport even of non-essential amino acids to support their increased proliferation rate. Besides their major role as protein synthesis precursors, the two proteinogenic sulfur-containing amino acids, methionine and cysteine, play specific biological functions. In human...
Data
Ras and MAPK activation state and expression levels in cellular models used in the paper: NIH3T3, NIH-RAS, NIH-RAS pGEF-DN and NIH-RAS pcDNA3. Expression levels of Total Ras proteins (A) and MAPKs p42 and p44 (B) in cell lysates of pull down assay. Antibodies directed against Ras (sc259 Santa Cruz), Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (Cel...
Data
Over-expression of GEF-DN reverts sensitivity to methionine limitation in NIH-RAS cells and partially rescues the defect in the expression of Slc6a15 gene encoding methionine transporter SBAT1. (A) Cell proliferation of NIH3T3, NIH-RAS, NIH-RAS pGEF-DN and NIH-RAS pcDNA3 cells grown in media with different concentrations of methionine and counted d...
Data
Mass duplication times under different nutritional perturbations. Mass duplication times (MDT) for NIH3T3 and NIH-RAS under different methionine or cysteine concentrations (possibly supplemented with GSH) were calculated on semi-logarithmic curves represented in Fig 1A and 1B. Then, Student’s t-test was performed on linear regression curves for eac...
Data
Methionine and cysteine metabolism in mouse fibroblasts. Methionine is partitioned between protein synthesis, de novo and recycling pathway, where it is converted to S-adenosylmethionine (SAM). SAM is converted to S-adenosylhomocysteine (SAH) during methylation of DNA and a large range of proteins and other molecules. SAH is then hydrolyzed to homo...
Data
Cell proliferation and qualitative ROS levels under different methionine concentrations and in cysteine-limiting or -depleted medium (possibly supplemented with antioxidants glutathione and MitoTEMPO or with GSH synthesis inhibitor BSO). For all the experiments, MitoTEMPO and buthionine sulfoximine (BSO) were used at the concentration of 10 μM and...
Data
Solute carriers differentially expressed between NIH3T3 and NIH-RAS cells. Genome-wide transcriptional profiling datasets for NIH3T3 and NIH-RAS cells (available in NCBI GEO database; accession GSM741354-GSM741361 for NIH3T3 cells and GSM741368-GSM741375 for NIH-RAS cells), previously obtained in our laboratory with an MG_U74Av2 Affymetrix Gene Chi...
Article
Full-text available
Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment...
Article
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Cell growth and proliferation require a complex series of tight-regulated and well-orchestrated events. Accordingly, proteins governing such events are evolutionary conserved, even among distant organisms. By contrast, it is more singular the case of "core functions" exerted by functional analogous proteins that are not homologous and do not share...
Article
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Introduction: Ras proteins are small GTPases molecular switches that cycle through two alternative conformational states, a GDP-bound inactive state and a GTP-bound active state. In the active state, Ras proteins interact with and modulate the activity of several downstream effectors regulating key cellular processes including proliferation, diffe...
Article
In eukaryotes DNA replication takes place in the S phase of the cell cycle. It initiates from hundreds to thousands of replication origins in a coordinated manner, in order to efficiently duplicate the genome. The sequence of events leading to the onset of DNA replication is conventionally divided in two interdependent processes: licensing—a proces...
Article
The multi-domain protein hSos1 plays a major role in cell growth and differentiation through its Ras-specific guanine nucleotide exchange domain whose complex regulation involves intra-molecular, inter-domain rearrangements. We present a stochastic mathematical model describing intra-molecular regulation of hSos1 activity. The population macroscopi...
Article
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Since mutations of Ras genes have a great incidence in human tumours, Ras oncoproteins are a major clinical target for the development of anticancer agents. We have developed synthetic molecules able to inhibit Ras activation. Here we present new, water-soluble Ras inhibitors composed by an aromatic pharmacofore moiety covalently linked to differen...
Article
Mutation of RAS genes is a critical event in the pathogenesis of different human tumors and in some developmental disorders. Here we present an arabinose-derived bicyclic compound displaying selective cytotoxicity in human colorectal cancer cells expressing K-Ras(G13D), that shows high intrinsic nucleotide exchange rate. We characterize binding of...
Article
By combining in the same molecule Ras-interacting aromatic moieties and a sugar, we prepared a water-soluble Ras ligand that binds Ras and inhibits guanine nucleotide exchange. With this compound it was possible to determine experimentally by a (15)N-edited HSQC NMR experiment the ligand-Ras binding interface.
Article
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Autophosphorylation of tyrosine residues on the cytoplasmic tail of the epidermal growth factor receptor (EGFR) upon ligand binding leads to recruitment of the Grb2/Sos complex to the activated receptor and to activation of the Ras pathway. The major aim of this study was to ascertain to which extent the EGFR module (receptor, Grb2, hSos1) could wo...
Article
The Ras-specific guanine nucleotide exchange region of hSos1 consists of two consecutive domains: the catalytic core (residues 742-1024) contains all residues binding to Ras, including the catalytic hairpin, and an upstream REM domain (residues 553-741), so called because it contains an evolutionary conserved Ras Exchange Motif (REM). We functional...
Article
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Mutational activation of ras genes is required for the onset and maintenance of different malignancies. Here we show, using a combination of molecular physiology, nutritional perturbations and transcriptional profiling, that full penetrance of phenotypes related to oncogenic Ras activation, including the shift of carbon metabolism towards fermentat...
Article
The role of tyrosyl phosphorylation/dephosphorylation in the budding yeast Saccharomyces cerevisiae, whose genome does not encode typical tyrosine kinases, has long remained elusive. Nevertheless, several protein kinases phosphorylating poly(TyrGlu) substrates have been identified. In this work, we use the expression of the low molecular weight tyr...
Article
Cdc25Mm is a mammalian Ras-specific guanine nucleotide exchange factor (GEF). By homology modeling we show that it shares with Sos-GEF the structure of the putative catalytic HI hairpin where the dominant negative T1184E mutation is located. Similarly to Cdc25MmT1184E, the isolated wild-type and mutant hairpins retain the ability to displace Ras-bo...
Article
The double-histone fold is a rare protein fold in which two consecutive regions characterized by the typical structure of histones assemble together, thus giving a histone pseudodimer. Previously, this fold was found in a few prokaryotic histones and in the regulatory region of guanine–nucleotide exchange factors of the Sos family. Standard methods...
Article
Full-text available
Mutational activation of the ras gene is critical for the onset of different malignant phenotypes. We constructed a dominant negative mutant (GEF-DN) of a Ras activator protein (guanine nucleotide-exchange factor) that upon over-expression in k-ras transformed NIH 3T3 fibroblasts strongly reduces intracellular Ras*GTP, reverting these cells to wild...
Article
Full-text available
Ras proteins are small GTPases playing a pivotal role in cell proliferation and differentiation. Their activation depends on the competing action of GTPase activating proteins and guanine nucleotide exchange factors (GEF). The properties of two dominant-negative mutants within the catalytic domains of the ras-specific GEF, CDC25Mm, are described. I...

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