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  1. Article ; Online: Upregulation of sphingosine kinase 1 in response to doxorubicin generates an angiogenic response via stabilization of Snail.

    Bonica, Joseph / Clarke, Christopher J / Obeid, Lina M / Luberto, Chiara / Hannun, Yusuf A

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2023  Volume 37, Issue 3, Page(s) e22787

    Abstract: Sphingosine kinase 1 (SK1) converts the pro-death lipid sphingosine to the pro-survival sphingosine-1-phosphate (S1P) and is upregulated in several cancers. DNA damaging agents, such as the chemotherapeutic doxorubicin (Dox), have been shown to degrade ... ...

    Abstract Sphingosine kinase 1 (SK1) converts the pro-death lipid sphingosine to the pro-survival sphingosine-1-phosphate (S1P) and is upregulated in several cancers. DNA damaging agents, such as the chemotherapeutic doxorubicin (Dox), have been shown to degrade SK1 protein in cancer cells, a process dependent on wild-type p53. As mutations in p53 are very common across several types of cancer, we evaluated the effects of Dox on SK1 in p53 mutant cancer cells. In the p53 mutant breast cancer cell line MDA-MB-231, we show that Dox treatment significantly increases SK1 protein and S1P. Using MDA-MB-231 cells with CRISPR-mediated knockout of SK1 or the selective SK1 inhibitor PF-543, we implicated SK1 in both Dox-induced migration and in a newly uncovered proangiogenic program induced by Dox. Mechanistically, inhibition of SK1 suppressed the induction of the cytokine BMP4 and of the EMT transcription factor Snail in response to Dox. Interestingly, induction of BMP4 by SK1 increased Snail levels following Dox treatment by stabilizing Snail protein. Furthermore, we found that SK1 was required for Dox-induced p38 MAP kinase phosphorylation and that active p38 MAPK in turn upregulated BMP4 and Snail, positioning p38 downstream of SK1 and upstream of BMP4/Snail. Modulating production of S1P by inhibition of de novo sphingolipid synthesis or knockdown of the S1P-degrading enzyme S1P lyase identified S1P as the sphingolipid activator of p38 in this model. This work establishes a novel angiogenic pathway in response to a commonly utilized chemotherapeutic and highlights the potential of SK1 as a secondary drug target for patients with p53 mutant cancer.
    MeSH term(s) Humans ; Up-Regulation ; Tumor Suppressor Protein p53/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Neoplasms ; Sphingolipids ; Doxorubicin/pharmacology ; Sphingosine/pharmacology ; Sphingosine/metabolism ; Lysophospholipids/pharmacology
    Chemical Substances sphingosine kinase (EC 2.7.1.-) ; Tumor Suppressor Protein p53 ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; Sphingolipids ; Doxorubicin (80168379AG) ; Sphingosine (NGZ37HRE42) ; Lysophospholipids
    Language English
    Publishing date 2023-03-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202201066R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Transcriptional Regulation of Sphingosine Kinase 1.

    Bonica, Joseph / Mao, Cungui / Obeid, Lina M / Hannun, Yusuf A

    Cells

    2020  Volume 9, Issue 11

    Abstract: Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate ... ...

    Abstract Once thought to be primarily structural in nature, sphingolipids have become increasingly appreciated as second messengers in a wide array of signaling pathways. Sphingosine kinase 1, or SK1, is one of two sphingosine kinases that phosphorylate sphingosine into sphingosine-1-phosphate (S1P). S1P is generally pro-inflammatory, pro-angiogenic, immunomodulatory, and pro-survival; therefore, high SK1 expression and activity have been associated with certain inflammatory diseases and cancer. It is thus important to develop an understanding of the regulation of SK1 expression and activity. In this review, we explore the current literature on SK1 transcriptional regulation, illustrating a complex system of transcription factors, cytokines, and even micro-RNAs (miRNAs) on the post transcriptional level.
    MeSH term(s) Cytokines/metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Hypoxia/pathology ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
    Chemical Substances Cytokines ; MicroRNAs ; RNA, Long Noncoding ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-)
    Language English
    Publishing date 2020-11-08
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9112437
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: A role for caspase‐2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells – implications for the CHK1‐suppressed pathway

    Carroll, Brittany L. / Bonica, Joseph / Shamseddine, Achraf A. / Hannun, Yusuf A. / Obeid, Lina M.

    FEBS Open Bio. 2018 Jan., v. 8, no. 1

    2018  

    Abstract: Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1‐phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have ... ...

    Abstract Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1‐phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have demonstrated that SK1 proteolysis occurs downstream of the tumor suppressor p53 in response to several DNA‐damaging agents. Moreover, loss of SK1 in p53‐knockout mice resulted in complete protection from thymic lymphoma, providing evidence that regulation of SK1 constitutes a major tumor suppressor function of p53. Given this profound phenotype, this study aimed to investigate the mechanism by which wild‐type p53 regulates proteolysis of SK1 in response to the DNA‐damaging agent doxorubicin in breast cancer cells. We find that p53‐mediated activation of caspase‐2 was required for SK1 proteolysis and that caspase‐2 activity significantly alters the levels of endogenous sphingolipids. As p53 is mutated in 50% of all cancers, we extended our studies to investigate whether SK1 is deregulated in the context of triple‐negative breast cancer cells (TNBC) harboring a mutation in p53. Indeed, caspase‐2 was not activated in these cells and SK1 was not degraded. Moreover, caspase‐2 activation was recently shown to be downstream of the CHK1‐suppressed pathway in p53‐mutant cells, whereby inhibition of the cell cycle kinase CHK1 leads to caspase‐2 activation and apoptosis. Indeed, knockdown and inhibition of CHK1 led to the loss of SK1 in p53‐mutant TNBC cells, providing evidence that SK1 may be the first identified effector of the CHK1‐suppressed pathway.
    Keywords angiogenesis ; apoptosis ; breast neoplasms ; caspase-2 ; cell cycle ; doxorubicin ; lymphoma ; mutation ; phenotype ; proteolysis ; sphingolipids ; sphingosine
    Language English
    Dates of publication 2018-01
    Size p. 27-40.
    Publishing place John Wiley & Sons, Ltd
    Document type Article
    Note JOURNAL ARTICLE
    ZDB-ID 2651702-4
    ISSN 2211-5463
    ISSN 2211-5463
    DOI 10.1002/2211-5463.12344
    Database NAL-Catalogue (AGRICOLA)

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  4. Article: A role for caspase-2 in sphingosine kinase 1 proteolysis in response to doxorubicin in breast cancer cells - implications for the CHK1-suppressed pathway.

    Carroll, Brittany L / Bonica, Joseph / Shamseddine, Achraf A / Hannun, Yusuf A / Obeid, Lina M

    FEBS open bio

    2017  Volume 8, Issue 1, Page(s) 27–40

    Abstract: Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1-phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have ... ...

    Abstract Sphingosine kinase 1 (SK1) is a lipid kinase whose activity produces sphingosine 1-phosphate, a prosurvival lipid associated with proliferation, angiogenesis, and invasion. SK1 overexpression has been observed in numerous cancers. Recent studies have demonstrated that SK1 proteolysis occurs downstream of the tumor suppressor p53 in response to several DNA-damaging agents. Moreover, loss of SK1 in p53-knockout mice resulted in complete protection from thymic lymphoma, providing evidence that regulation of SK1 constitutes a major tumor suppressor function of p53. Given this profound phenotype, this study aimed to investigate the mechanism by which wild-type p53 regulates proteolysis of SK1 in response to the DNA-damaging agent doxorubicin in breast cancer cells. We find that p53-mediated activation of caspase-2 was required for SK1 proteolysis and that caspase-2 activity significantly alters the levels of endogenous sphingolipids. As p53 is mutated in 50% of all cancers, we extended our studies to investigate whether SK1 is deregulated in the context of triple-negative breast cancer cells (TNBC) harboring a mutation in p53. Indeed, caspase-2 was not activated in these cells and SK1 was not degraded. Moreover, caspase-2 activation was recently shown to be downstream of the CHK1-suppressed pathway in p53-mutant cells, whereby inhibition of the cell cycle kinase CHK1 leads to caspase-2 activation and apoptosis. Indeed, knockdown and inhibition of CHK1 led to the loss of SK1 in p53-mutant TNBC cells, providing evidence that SK1 may be the first identified effector of the CHK1-suppressed pathway.
    Language English
    Publishing date 2017-12-08
    Publishing country England
    Document type Journal Article
    ISSN 2211-5463
    ISSN 2211-5463
    DOI 10.1002/2211-5463.12344
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Bioactive sphingolipids: Advancements and contributions from the laboratory of Dr. Lina M. Obeid.

    Velazquez, Fabiola N / Hernandez-Corbacho, Maria / Trayssac, Magali / Stith, Jeffrey L / Bonica, Joseph / Jean, Bernandie / Pulkoski-Gross, Michael J / Carroll, Brittany L / Salama, Mohamed F / Hannun, Yusuf A / Snider, Ashley J

    Cellular signalling

    2020  Volume 79, Page(s) 109875

    Abstract: Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been ... ...

    Abstract Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. In this review, we will discuss the contributions from the laboratory of Dr. Lina M. Obeid that have defined the roles for several bioactive sphingolipids in signaling and disease with an emphasis on her work defining SK1 in cellular fates and pathobiologies including proliferation, senescence, apoptosis, and inflammation.
    MeSH term(s) Aging/genetics ; Aging/metabolism ; Aging/pathology ; Animals ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Laboratories ; Lysophospholipids/genetics ; Lysophospholipids/metabolism ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Signal Transduction ; Sphingolipids/genetics ; Sphingolipids/metabolism ; Sphingosine/analogs & derivatives ; Sphingosine/genetics ; Sphingosine/metabolism
    Chemical Substances Lysophospholipids ; Neoplasm Proteins ; Sphingolipids ; sphingosine 1-phosphate (26993-30-6) ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2020-12-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1002702-6
    ISSN 1873-3913 ; 0898-6568
    ISSN (online) 1873-3913
    ISSN 0898-6568
    DOI 10.1016/j.cellsig.2020.109875
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    Zs.A 2579: Show issues Location:
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  6. Article ; Online: Novel Metabolic Abnormalities in the Tricarboxylic Acid Cycle in Peripheral Cells From Huntington's Disease Patients.

    Naseri, Nima N / Bonica, Joseph / Xu, Hui / Park, Larry C / Arjomand, Jamshid / Chen, Zhengming / Gibson, Gary E

    PloS one

    2016  Volume 11, Issue 9, Page(s) e0160384

    Abstract: Metabolic dysfunction is well-documented in Huntington's disease (HD). However, the link between the mutant huntingtin (mHTT) gene and the pathology is unknown. The tricarboxylic acid (TCA) cycle is the main metabolic pathway for the production of NADH ... ...

    Abstract Metabolic dysfunction is well-documented in Huntington's disease (HD). However, the link between the mutant huntingtin (mHTT) gene and the pathology is unknown. The tricarboxylic acid (TCA) cycle is the main metabolic pathway for the production of NADH for conversion to ATP via the electron transport chain (ETC). The objective of this study was to test for differences in enzyme activities, mRNAs and protein levels related to the TCA cycle between lymphoblasts from healthy subjects and from patients with HD. The experiments utilize the advantages of lymphoblasts to reveal new insights about HD. The large quantity of homogeneous cell populations permits multiple dynamic measures to be made on exactly comparable tissues. The activities of nine enzymes related to the TCA cycle and the expression of twenty-nine mRNAs encoding for these enzymes and enzyme complexes were measured. Cells were studied under baseline conditions and during metabolic stress. The results support our recent findings that the activities of the pyruvate dehydrogenase complex (PDHC) and succinate dehydrogenase (SDH) are elevated in HD. The data also show a large unexpected depression in MDH activities. Furthermore, message levels for isocitrate dehydrogenase 1 (IDH1) were markedly increased in in HD lymphoblasts and were responsive to treatments. The use of lymphoblasts allowed us to clarify that the reported decrease in aconitase activity in HD autopsy brains is likely due to secondary hypoxic effects. These results demonstrate the mRNA and enzymes of the TCA cycle are critical therapeutic targets that have been understudied in HD.
    MeSH term(s) Adult ; Case-Control Studies ; Cell Death/drug effects ; Cell Death/genetics ; Cell Line ; Citric Acid Cycle ; Energy Metabolism ; Female ; Gene Expression ; Gene Expression Regulation, Enzymologic ; Humans ; Huntington Disease/genetics ; Huntington Disease/metabolism ; Male ; Middle Aged ; Mitochondria/metabolism ; Oxidative Stress/drug effects ; Oxidative Stress/genetics ; Pyruvate Dehydrogenase Complex/genetics ; Pyruvate Dehydrogenase Complex/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Sodium Cyanide/pharmacology ; Stress, Physiological ; Trinucleotide Repeats
    Chemical Substances Pyruvate Dehydrogenase Complex ; RNA, Messenger ; Sodium Cyanide (O5DDB9Z95G)
    Language English
    Publishing date 2016-09-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0160384
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  7. Article ; Online: Abnormalities in the tricarboxylic Acid cycle in Huntington disease and in a Huntington disease mouse model.

    Naseri, Nima N / Xu, Hui / Bonica, Joseph / Vonsattel, Jean Paul G / Cortes, Etty P / Park, Larry C / Arjomand, Jamshid / Gibson, Gary E

    Journal of neuropathology and experimental neurology

    2015  Volume 74, Issue 6, Page(s) 527–537

    Abstract: Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease, and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of ... ...

    Abstract Glucose metabolism is reduced in the brains of patients with Huntington disease (HD). The mechanisms underlying this deficit, its link to the pathology of the disease, and the vulnerability of the striatum in HD remain unknown. Abnormalities in some of the key mitochondrial enzymes involved in glucose metabolism, including the pyruvate dehydrogenase complex (PDHC) and the tricarboxylic acid (TCA) cycle, may contribute to these deficits. Here, activities for these enzymes and select protein levels were measured in human postmortem cortex and in striatum and cortex of an HD mouse model (Q175); mRNA levels encoding for these enzymes were also measured in the Q175 mouse cortex. The activities of PDHC and nearly all of the TCA cycle enzymes were dramatically lower (-50% to 90%) in humans than in mice. The activity of succinate dehydrogenase increased with HD in human (35%) and mouse (23%) cortex. No other changes were detected in the human HD cortex or mouse striatum. In Q175 cortex, there were increased activities of PDHC (+12%) and aconitase (+32%). Increased mRNA levels for succinyl thiokinase (+88%) and isocitrate dehydrogenase (+64%) suggested an upregulation of the TCA cycle. These patterns of change differ from those reported in other diseases, which may offer unique metabolic therapeutic opportunities for HD patients.
    MeSH term(s) Acyltransferases/genetics ; Acyltransferases/metabolism ; Aged ; Aged, 80 and over ; Animals ; Cerebral Cortex/enzymology ; Citric Acid Cycle/physiology ; Corpus Striatum/enzymology ; Dihydrolipoamide Dehydrogenase/genetics ; Dihydrolipoamide Dehydrogenase/metabolism ; Disease Models, Animal ; Female ; Humans ; Huntington Disease/enzymology ; Huntington Disease/pathology ; Huntington Disease/physiopathology ; Ketoglutarate Dehydrogenase Complex/genetics ; Ketoglutarate Dehydrogenase Complex/metabolism ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Mutation/genetics ; Postmortem Changes ; Pyruvate Dehydrogenase Complex/genetics ; Pyruvate Dehydrogenase Complex/metabolism ; Retrospective Studies
    Chemical Substances Pyruvate Dehydrogenase Complex ; Ketoglutarate Dehydrogenase Complex (EC 1.2.4.2) ; Dihydrolipoamide Dehydrogenase (EC 1.8.1.4) ; Acyltransferases (EC 2.3.-) ; dihydrolipoamide succinyltransferase (EC 2.3.1.61)
    Language English
    Publishing date 2015-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3088-0
    ISSN 1554-6578 ; 0022-3069
    ISSN (online) 1554-6578
    ISSN 0022-3069
    DOI 10.1097/NEN.0000000000000197
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    Ui II Zs.134: Show issues Location:
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