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  1. Article: Inhibition of Heme Export and/or Heme Synthesis Potentiates Metformin Anti-Proliferative Effect on Cancer Cell Lines.

    Allocco, Anna Lucia / Bertino, Francesca / Petrillo, Sara / Chiabrando, Deborah / Riganti, Chiara / Bardelli, Alberto / Altruda, Fiorella / Fiorito, Veronica / Tolosano, Emanuela

    Cancers

    2022  Volume 14, Issue 5

    Abstract: Cancer is one of the leading causes of mortality worldwide. Beyond standard therapeutic options, whose effectiveness is often reduced by drug resistance, repurposing of the antidiabetic drug metformin appears promising. Heme metabolism plays a pivotal ... ...

    Abstract Cancer is one of the leading causes of mortality worldwide. Beyond standard therapeutic options, whose effectiveness is often reduced by drug resistance, repurposing of the antidiabetic drug metformin appears promising. Heme metabolism plays a pivotal role in the control of metabolic adaptations that sustain cancer cell proliferation. Recently, we demonstrated the existence of a functional axis between the heme synthetic enzyme ALAS1 and the heme exporter FLVCR1a exploited by cancer cells to down-modulate oxidative metabolism. In colorectal cancer cell lines, the inhibition of heme synthesis-export system was associated with reduced proliferation and survival. Here, we aim to assess whether the inhibition of the heme synthesis-export system affects the sensitivity of colorectal cancer cells to metformin. Our data demonstrate that the inhibition of this system, either by blocking heme efflux with a
    Language English
    Publishing date 2022-02-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14051230
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Flvcr1a deficiency promotes heme-based energy metabolism dysfunction in skeletal muscle.

    Mistretta, Miriam / Fiorito, Veronica / Allocco, Anna Lucia / Ammirata, Giorgia / Hsu, Myriam Y / Digiovanni, Sabrina / Belicchi, Marzia / Napoli, Laura / Ripolone, Michela / Trombetta, Elena / Mauri, PierLuigi / Farini, Andrea / Meregalli, Mirella / Villa, Chiara / Porporato, Paolo Ettore / Miniscalco, Barbara / Crich, Simonetta Geninatti / Riganti, Chiara / Torrente, Yvan /
    Tolosano, Emanuela

    Cell reports

    2024  Volume 43, Issue 3, Page(s) 113854

    Abstract: The definition of cell metabolic profile is essential to ensure skeletal muscle fiber heterogeneity and to achieve a proper equilibrium between the self-renewal and commitment of satellite stem cells. Heme sustains several biological functions, including ...

    Abstract The definition of cell metabolic profile is essential to ensure skeletal muscle fiber heterogeneity and to achieve a proper equilibrium between the self-renewal and commitment of satellite stem cells. Heme sustains several biological functions, including processes profoundly implicated with cell metabolism. The skeletal muscle is a significant heme-producing body compartment, but the consequences of impaired heme homeostasis on this tissue have been poorly investigated. Here, we generate a skeletal-muscle-specific feline leukemia virus subgroup C receptor 1a (FLVCR1a) knockout mouse model and show that, by sustaining heme synthesis, FLVCR1a contributes to determine the energy phenotype in skeletal muscle cells and to modulate satellite cell differentiation and muscle regeneration.
    MeSH term(s) Mice ; Animals ; Membrane Transport Proteins/metabolism ; Heme/metabolism ; Mice, Knockout ; Muscle, Skeletal/metabolism ; Energy Metabolism ; Satellite Cells, Skeletal Muscle/metabolism ; Cell Differentiation/physiology
    Chemical Substances Membrane Transport Proteins ; Heme (42VZT0U6YR)
    Language English
    Publishing date 2024-02-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2024.113854
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Endothelial Heme Dynamics Drive Cancer Cell Metabolism by Shaping the Tumor Microenvironment.

    Petrillo, Sara / De Giorgio, Francesco / Kopecka, Joanna / Genova, Tullio / Fiorito, Veronica / Allocco, Anna Lucia / Bertino, Francesca / Chiabrando, Deborah / Mussano, Federico / Altruda, Fiorella / Munaron, Luca / Riganti, Chiara / Tolosano, Emanuela

    Biomedicines

    2021  Volume 9, Issue 11

    Abstract: The crosstalk among cancer cells (CCs) and stromal cells within the tumor microenvironment (TME) has a prominent role in cancer progression. The significance of endothelial cells (ECs) in this scenario relies on multiple vascular functions. By forming ... ...

    Abstract The crosstalk among cancer cells (CCs) and stromal cells within the tumor microenvironment (TME) has a prominent role in cancer progression. The significance of endothelial cells (ECs) in this scenario relies on multiple vascular functions. By forming new blood vessels, ECs support tumor growth. In addition to their angiogenic properties, tumor-associated ECs (TECs) establish a unique vascular niche that actively modulates cancer development by shuttling a selected pattern of factors and metabolites to the CC. The profile of secreted metabolites is strictly dependent on the metabolic status of the cell, which is markedly perturbed in TECs. Recent evidence highlights the involvement of heme metabolism in the regulation of energy metabolism in TECs. The present study shows that interfering with endothelial heme metabolism by targeting the cell membrane heme exporter Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a) in TECs, resulted in enhanced fatty acid oxidation (FAO). Moreover, FAO-derived acetyl-CoA was partly consumed through ketogenesis, resulting in ketone bodies (KBs) accumulation in FLVCR1a-deficient TECs. Finally, the results from this study also demonstrate that TECs-derived KBs can be secreted in the extracellular environment, inducing a metabolic rewiring in the CC. Taken together, these data may contribute to finding new metabolic vulnerabilities for cancer therapy.
    Language English
    Publishing date 2021-10-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines9111557
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation.

    Fiorito, Veronica / Allocco, Anna Lucia / Petrillo, Sara / Gazzano, Elena / Torretta, Simone / Marchi, Saverio / Destefanis, Francesca / Pacelli, Consiglia / Audrito, Valentina / Provero, Paolo / Medico, Enzo / Chiabrando, Deborah / Porporato, Paolo Ettore / Cancelliere, Carlotta / Bardelli, Alberto / Trusolino, Livio / Capitanio, Nazzareno / Deaglio, Silvia / Altruda, Fiorella /
    Pinton, Paolo / Cardaci, Simone / Riganti, Chiara / Tolosano, Emanuela

    Cell reports

    2021  Volume 35, Issue 11, Page(s) 109252

    Abstract: Heme is an iron-containing porphyrin of vital importance for cell energetic metabolism. High rates of heme synthesis are commonly observed in proliferating cells. Moreover, the cell-surface heme exporter feline leukemia virus subgroup C receptor 1a ( ... ...

    Abstract Heme is an iron-containing porphyrin of vital importance for cell energetic metabolism. High rates of heme synthesis are commonly observed in proliferating cells. Moreover, the cell-surface heme exporter feline leukemia virus subgroup C receptor 1a (FLVCR1a) is overexpressed in several tumor types. However, the reasons why heme synthesis and export are enhanced in highly proliferating cells remain unknown. Here, we illustrate a functional axis between heme synthesis and heme export: heme efflux through the plasma membrane sustains heme synthesis, and implementation of the two processes down-modulates the tricarboxylic acid (TCA) cycle flux and oxidative phosphorylation. Conversely, inhibition of heme export reduces heme synthesis and promotes the TCA cycle fueling and flux as well as oxidative phosphorylation. These data indicate that the heme synthesis-export system modulates the TCA cycle and oxidative metabolism and provide a mechanistic basis for the observation that both processes are enhanced in cells with high-energy demand.
    MeSH term(s) Animals ; Biological Transport ; Caco-2 Cells ; Citric Acid Cycle ; Heme/biosynthesis ; Heme/metabolism ; Humans ; Membrane Transport Proteins/metabolism ; Mice, Inbred C57BL ; Mice, SCID ; Oxidative Phosphorylation ; Receptors, Virus/metabolism ; Xenograft Model Antitumor Assays ; Mice
    Chemical Substances FLVCR1 protein, human ; Membrane Transport Proteins ; Receptors, Virus ; Heme (42VZT0U6YR)
    Language English
    Publishing date 2021-06-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.109252
    Database MEDical Literature Analysis and Retrieval System OnLINE

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