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  1. Article ; Online: FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer.

    Wilde, Blake R / Chakraborty, Nishma / Matulionis, Nedas / Hernandez, Stephanie / Ueno, Daiki / Gee, Michayla E / Esplin, Edward D / Ouyang, Karen / Nykamp, Keith / Shuch, Brian / Christofk, Heather R

    Cancer discovery

    2023  Volume 13, Issue 9, Page(s) 2072–2089

    Abstract: Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. ... ...

    Abstract Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.
    Significance: This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers. This article is featured in Selected Articles from This Issue, p. 1949.
    MeSH term(s) Humans ; Fumarate Hydratase/genetics ; Fumarate Hydratase/metabolism ; Virulence ; Carcinoma, Renal Cell/pathology ; Kidney Neoplasms/genetics ; Skin Neoplasms/genetics ; Purines
    Chemical Substances Fumarate Hydratase (EC 4.2.1.2) ; Purines
    Language English
    Publishing date 2023-03-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-22-0874
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6916: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Atlas of fetal metabolism during mid-to-late gestation and diabetic pregnancy.

    Perez-Ramirez, Cesar A / Nakano, Haruko / Law, Richard C / Matulionis, Nedas / Thompson, Jennifer / Pfeiffer, Andrew / Park, Junyoung O / Nakano, Atsushi / Christofk, Heather R

    Cell

    2023  Volume 187, Issue 1, Page(s) 204–215.e14

    Abstract: Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo ... ...

    Abstract Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using
    MeSH term(s) Animals ; Female ; Mice ; Pregnancy ; Diabetes Mellitus/metabolism ; Fetus/metabolism ; Glucose/metabolism ; Placenta/metabolism ; Diabetes, Gestational/metabolism
    Chemical Substances Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2023-12-08
    Publishing country United States
    Document type Review ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2023.11.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1167: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 58: Show issues

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  3. Article ; Online: A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's ataxia.

    Campos, Oscar A / Attar, Narsis / Cheng, Chen / Vogelauer, Maria / Mallipeddi, Nathan V / Schmollinger, Stefan / Matulionis, Nedas / Christofk, Heather R / Merchant, Sabeeha S / Kurdistani, Siavash K

    Science advances

    2021  Volume 7, Issue 51, Page(s) eabj9889

    Abstract: Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. A source of damage to Fe-S clusters is cuprous ( ... ...

    Abstract Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. A source of damage to Fe-S clusters is cuprous (Cu
    Language English
    Publishing date 2021-12-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abj9889
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition.

    Mullen, Peter J / Garcia, Gustavo / Purkayastha, Arunima / Matulionis, Nedas / Schmid, Ernst W / Momcilovic, Milica / Sen, Chandani / Langerman, Justin / Ramaiah, Arunachalam / Shackelford, David B / Damoiseaux, Robert / French, Samuel W / Plath, Kathrin / Gomperts, Brigitte N / Arumugaswami, Vaithilingaraja / Christofk, Heather R

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1876

    Abstract: Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 ...

    Abstract Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.
    MeSH term(s) Animals ; Benzamides/pharmacology ; COVID-19/pathology ; Cell Line ; Chlorocebus aethiops ; Citric Acid Cycle/physiology ; Glucose/metabolism ; Glutamine/metabolism ; HEK293 Cells ; Humans ; Lung/metabolism ; Lung/virology ; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Morpholines/pharmacology ; Naphthyridines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology ; Pyruvate Carboxylase/biosynthesis ; SARS-CoV-2/metabolism ; Vero Cells ; Virus Replication/drug effects
    Chemical Substances 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one ; Benzamides ; Morpholines ; Naphthyridines ; Protein Kinase Inhibitors ; Pyrimidines ; vistusertib (0BSC3P4H5X) ; Glutamine (0RH81L854J) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Pyruvate Carboxylase (EC 6.4.1.1) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-03-25
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-22166-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.

    Crowell, Preston D / Giafaglione, Jenna M / Jones, Anthony E / Nunley, Nicholas M / Hashimoto, Takao / Delcourt, Amelie M L / Petcherski, Anton / Agrawal, Raag / Bernard, Matthew J / Diaz, Johnny A / Heering, Kylie Y / Huang, Rong Rong / Low, Jin-Yih / Matulionis, Nedas / Navone, Nora M / Ye, Huihui / Zoubeidi, Amina / Christofk, Heather R / Rettig, Matthew B /
    Reiter, Robert E / Haffner, Michael C / Boutros, Paul C / Shirihai, Orian S / Divakaruni, Ajit S / Goldstein, Andrew S

    Cell reports

    2023  Volume 42, Issue 10, Page(s) 113221

    Abstract: Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells ... ...

    Abstract Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.
    MeSH term(s) Humans ; Male ; Androgens/metabolism ; Cell Line, Tumor ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms, Castration-Resistant/genetics ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Receptors, Androgen/drug effects ; Receptors, Androgen/metabolism ; Signal Transduction
    Chemical Substances Androgens ; Proto-Oncogene Proteins c-myc ; Receptors, Androgen
    Language English
    Publishing date 2023-10-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2023.113221
    Database MEDical Literature Analysis and Retrieval System OnLINE

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