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  1. Article ; Online: Cyclic AMP-Epac signaling pathway contributes to repression of PUMA transcription in melanoma cells.

    Lakhter, Alexander J / Naidu, Samisubbu R

    Melanoma research

    2017  Volume 27, Issue 5, Page(s) 411–416

    Abstract: The universal second messenger cAMP regulates numerous cellular processes. Although the cAMP-signaling pathway leads to induction of gene transcription, it remains unknown whether this pathway contributes toward suppression of transcription. Here, we ... ...

    Abstract The universal second messenger cAMP regulates numerous cellular processes. Although the cAMP-signaling pathway leads to induction of gene transcription, it remains unknown whether this pathway contributes toward suppression of transcription. Here, we show that blockade of cAMP signaling using MDL12330A led to an increase in PUMA transcript levels, but not p21 in melanoma cells. cAMP downstream component Epac activation was essential for suppression of PUMA transcription as an Epac agonist reversed the effects of MDL12330A. These results suggest that transcriptional repression is one of the functions of the cAMP-Epac signaling pathway.
    MeSH term(s) Apoptosis Regulatory Proteins/biosynthesis ; Apoptosis Regulatory Proteins/genetics ; Cell Line, Tumor ; Cyclic AMP/antagonists & inhibitors ; Cyclic AMP/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Guanine Nucleotide Exchange Factors/agonists ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Imines/pharmacology ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins/genetics ; Second Messenger Systems/drug effects ; Second Messenger Systems/genetics ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Transcription, Genetic/drug effects
    Chemical Substances Apoptosis Regulatory Proteins ; BBC3 protein, human ; CDKN1A protein, human ; Cyclin-Dependent Kinase Inhibitor p21 ; Guanine Nucleotide Exchange Factors ; Imines ; Proto-Oncogene Proteins ; RAPGEF3 protein, human ; RMI 12330A (82985-31-7) ; Cyclic AMP (E0399OZS9N)
    Language English
    Publishing date 2017
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1095779-0
    ISSN 1473-5636 ; 0960-8931
    ISSN (online) 1473-5636
    ISSN 0960-8931
    DOI 10.1097/CMR.0000000000000363
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3378: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Minireview: Emerging Roles for Extracellular Vesicles in Diabetes and Related Metabolic Disorders.

    Lakhter, Alexander J / Sims, Emily K

    Molecular endocrinology (Baltimore, Md.)

    2015  Volume 29, Issue 11, Page(s) 1535–1548

    Abstract: Extracellular vesicles (EVs), membrane-contained vesicles released by most cell types, have attracted a large amount of research interest over the past decade. Because of their ability to transfer cargo via regulated processes, causing functional impacts ...

    Abstract Extracellular vesicles (EVs), membrane-contained vesicles released by most cell types, have attracted a large amount of research interest over the past decade. Because of their ability to transfer cargo via regulated processes, causing functional impacts on recipient cells, these structures may play important roles in cell-cell communication and have implications in the physiology of numerous organ systems. In addition, EVs have been described in most human biofluids and have wide potential as relatively noninvasive biomarkers of various pathologic conditions. Specifically, EVs produced by the pancreatic β-cell have been demonstrated to regulate physiologic and pathologic responses to β-cell stress, including β-cell proliferation and apoptosis. β-Cell EVs are also capable of interacting with immune cells and may contribute to the activation of autoimmune processes that trigger or propagate β-cell inflammation and destruction during the development of diabetes. EVs from adipose tissue have been shown to contribute to the development of the chronic inflammation and insulin resistance associated with obesity and metabolic syndrome via interactions with other adipose, liver, and muscle cells. Circulating EVs may also serve as biomarkers for metabolic derangements and complications associated with diabetes. This minireview describes the properties of EVs in general, followed by a more focused review of the literature describing EVs affecting the β-cell, β-cell autoimmunity, and the development of insulin resistance, which all have the potential to affect development of type 1 or type 2 diabetes.
    MeSH term(s) Adipose Tissue/metabolism ; Autoimmunity/physiology ; Cell Communication/physiology ; Diabetes Mellitus/pathology ; Extracellular Vesicles/physiology ; Humans ; Inflammation/pathology ; Insulin-Secreting Cells/metabolism ; Metabolic Syndrome/pathology ; MicroRNAs/genetics ; Obesity/pathology ; Protein Transport/physiology
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2015-09-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 639167-9
    ISSN 1944-9917 ; 0888-8809
    ISSN (online) 1944-9917
    ISSN 0888-8809
    DOI 10.1210/me.2015-1206
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2.

    Shankar Babu, Mani / Mahanta, Sailendra / Lakhter, Alexander J / Hato, Takashi / Paul, Subhankar / Naidu, Samisubbu R

    PloS one

    2018  Volume 13, Issue 2, Page(s) e0191419

    Abstract: Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for ... ...

    Abstract Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity-binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells.
    MeSH term(s) Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Inhibitors/pharmacology ; Glycolysis/drug effects ; Humans ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Mitochondria/metabolism ; Models, Molecular ; Naphthoquinones/pharmacology ; Oxygen Consumption/drug effects ; Pyruvate Kinase/antagonists & inhibitors ; Pyruvate Kinase/chemistry
    Chemical Substances Antineoplastic Agents, Phytogenic ; Enzyme Inhibitors ; Naphthoquinones ; shikonin (3IK6592UBW) ; lapachol (B221938VB6) ; Pyruvate Kinase (EC 2.7.1.40)
    Language English
    Publishing date 2018
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0191419
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Golgi Associated HIF1a Serves as a Reserve in Melanoma Cells.

    Lakhter, Alexander J / Lahm, Tim / Broxmeyer, Hal E / Naidu, Samisubbu R

    Journal of cellular biochemistry

    2016  Volume 117, Issue 4, Page(s) 853–859

    Abstract: Hypoxia-inducible factor-1alpha (HIF1a) is a key transcriptional regulator that enables cellular metabolic adaptation to low levels of oxygen. Multiple mechanisms, including lysosomal degradation, control the levels of HIF1a protein. Here we show that ... ...

    Abstract Hypoxia-inducible factor-1alpha (HIF1a) is a key transcriptional regulator that enables cellular metabolic adaptation to low levels of oxygen. Multiple mechanisms, including lysosomal degradation, control the levels of HIF1a protein. Here we show that HIF1a protein degradation is resistant to lysosomal inhibition and that HIF1a is associated with the Golgi compartment in melanoma cells. Although pharmacological inhibitors of prolyl hydroxylation, neddylation and the proteasome inhibited degradation of HIF1a, attenuation of lysosomal activity with chloroquine did not alter the levels of HIF1a or its association with Golgi. Pharmacological disruption of Golgi resulted in nuclear accumulation of HIF1a. However, blockade of ER-Golgi protein transport in hypoxia reduced the transcript levels of HIF1a target genes. These findings suggest a possible role for the oxygen-dependent protein folding process from the ER-Golgi compartment in fine-tuning HIF1a transcriptional output.
    MeSH term(s) Amino Acids, Dicarboxylic/pharmacology ; Cell Hypoxia ; Cell Line, Tumor ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Chloroquine/pharmacology ; Cyclopentanes/pharmacology ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/metabolism ; Gene Expression Regulation, Neoplastic ; Golgi Apparatus/drug effects ; Golgi Apparatus/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lysosomes/drug effects ; Lysosomes/metabolism ; Melanocytes/drug effects ; Melanocytes/metabolism ; Melanocytes/pathology ; Oxygen/pharmacology ; Prolyl Hydroxylases/genetics ; Prolyl Hydroxylases/metabolism ; Prolyl-Hydroxylase Inhibitors/pharmacology ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/metabolism ; Protein Folding ; Protein Transport ; Proteolysis/drug effects ; Pyrimidines/pharmacology ; RNA, Messenger/antagonists & inhibitors ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction ; Transcription, Genetic
    Chemical Substances Amino Acids, Dicarboxylic ; Cyclopentanes ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Prolyl-Hydroxylase Inhibitors ; Pyrimidines ; RNA, Messenger ; Chloroquine (886U3H6UFF) ; Prolyl Hydroxylases (EC 1.14.11.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; pevonedistat (S3AZD8D215) ; Oxygen (S88TT14065) ; oxalylglycine (VVW38EB8YS)
    Language English
    Publishing date 2016-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.25381
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    Zs.A 1114: Show issues Location:
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  5. Article ; Online: PIASy-mediated Tip60 sumoylation regulates p53-induced autophagy.

    Naidu, Samisubbu R / Lakhter, Alexander J / Androphy, Elliot J

    Cell cycle (Georgetown, Tex.)

    2012  Volume 11, Issue 14, Page(s) 2717–2728

    Abstract: Posttranslational modifications of p53 integrate diverse stress signals and regulate its activity, but their combinatorial contribution to overall p53 function is not clear. We investigated the roles of lysine (K) acetylation and sumoylation on p53 and ... ...

    Abstract Posttranslational modifications of p53 integrate diverse stress signals and regulate its activity, but their combinatorial contribution to overall p53 function is not clear. We investigated the roles of lysine (K) acetylation and sumoylation on p53 and their relation to apoptosis and autophagy. Here we describe the collaborative role of the SUMO E3 ligase PIASy and the lysine acetyltransferase Tip60 in p53-mediated autophagy. PIASy binding to p53 and PIASy-activated Tip60 lead to K386 sumoylation and K120 acetylation of p53, respectively. Even though these two modifications are not dependent on each other, together they act as a "binary death signal" to promote cytoplasmic accumulation of p53 and execution of PUMA-independent autophagy. PIASy-induced Tip60 sumoylation augments p53 K120 acetylation and apoptosis. In addition to p14(ARF) inactivation, impairment in this intricate signaling may explain why p53 mutations are not found in nearly 50% of malignancies.
    MeSH term(s) Acetylation ; Apoptosis ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Autophagy ; Cell Line ; HCT116 Cells ; Histone Acetyltransferases/metabolism ; Humans ; Lysine Acetyltransferase 5 ; Mutation ; Poly-ADP-Ribose Binding Proteins ; Protein Binding ; Protein Inhibitors of Activated STAT/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Sumoylation ; Tumor Suppressor Protein p14ARF/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Apoptosis Regulatory Proteins ; BBC3 protein, human ; PIAS4 protein, human ; Poly-ADP-Ribose Binding Proteins ; Protein Inhibitors of Activated STAT ; Proto-Oncogene Proteins ; Tumor Suppressor Protein p14ARF ; Tumor Suppressor Protein p53 ; Histone Acetyltransferases (EC 2.3.1.48) ; KAT5 protein, human (EC 2.3.1.48) ; Lysine Acetyltransferase 5 (EC 2.3.1.48)
    Language English
    Publishing date 2012-07-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.21091
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5881: Show issues Location:
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  6. Article ; Online: Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth.

    Lakhter, Alexander J / Hamilton, James / Konger, Raymond L / Brustovetsky, Nickolay / Broxmeyer, Hal E / Naidu, Samisubbu R

    The Journal of biological chemistry

    2016  Volume 291, Issue 42, Page(s) 21869–21879

    Abstract: Tumors rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, the relative contribution of acetate ... ...

    Abstract Tumors rely on multiple nutrients to meet cellular bioenergetics and macromolecular synthesis demands of rapidly dividing cells. Although the role of glucose and glutamine in cancer metabolism is well understood, the relative contribution of acetate metabolism remains to be clarified. We show that glutamine supplementation is not sufficient to prevent loss of cell viability in a subset of glucose-deprived melanoma cells, but synergizes with acetate to support cell survival. Glucose-deprived melanoma cells depend on both oxidative phosphorylation and acetate metabolism for cell survival. Acetate supplementation significantly contributed to maintenance of ATP levels in glucose-starved cells. Unlike acetate, short chain fatty acids such as butyrate and propionate failed to prevent loss of cell viability from glucose deprivation. In vivo studies revealed that in addition to nucleo-cytoplasmic acetate assimilating enzyme ACSS2, mitochondrial ACSS1 was critical for melanoma tumor growth in mice. Our data indicate that acetate metabolism may be a potential therapeutic target for BRAF mutant melanoma.
    MeSH term(s) Acetates/metabolism ; Acetyl-CoA Carboxylase/genetics ; Acetyl-CoA Carboxylase/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Butyric Acid/metabolism ; Cell Line, Tumor ; Female ; Glucose/genetics ; Glucose/metabolism ; Heterografts ; Humans ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Melanoma/therapy ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mutation ; Neoplasm Transplantation ; Oxidative Phosphorylation ; Propionates/metabolism ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism
    Chemical Substances Acetates ; Propionates ; Butyric Acid (107-92-6) ; Adenosine Triphosphate (8L70Q75FXE) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; ACACB protein, human (EC 6.4.1.2) ; Acetyl-CoA Carboxylase (EC 6.4.1.2) ; Glucose (IY9XDZ35W2) ; propionic acid (JHU490RVYR)
    Language English
    Publishing date 2016-08-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M115.712166
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    Uc I Zs.108: Show issues Location:
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  7. Article ; Online: Beta cell extracellular vesicle miR-21-5p cargo is increased in response to inflammatory cytokines and serves as a biomarker of type 1 diabetes.

    Lakhter, Alexander J / Pratt, Rachel E / Moore, Rachel E / Doucette, Kaitlin K / Maier, Bernhard F / DiMeglio, Linda A / Sims, Emily K

    Diabetologia

    2018  Volume 61, Issue 5, Page(s) 1124–1134

    Abstract: Aims/hypothesis: Improved biomarkers are acutely needed for the detection of developing type 1 diabetes, prior to critical loss of beta cell mass. We previously demonstrated that elevated beta cell microRNA 21-5p (miR-21-5p) in rodent and human models ... ...

    Abstract Aims/hypothesis: Improved biomarkers are acutely needed for the detection of developing type 1 diabetes, prior to critical loss of beta cell mass. We previously demonstrated that elevated beta cell microRNA 21-5p (miR-21-5p) in rodent and human models of type 1 diabetes increased beta cell apoptosis. We hypothesised that the inflammatory milieu of developing diabetes may also increase miR-21-5p in beta cell extracellular vesicle (EV) cargo and that circulating EV miR-21-5p would be increased during type 1 diabetes development.
    Methods: MIN6 and EndoC-βH1 beta cell lines and human islets were treated with IL-1β, IFN-γ and TNF-α to mimic the inflammatory milieu of early type 1 diabetes. Serum was collected weekly from 8-week-old female NOD mice until diabetes onset. Sera from a cross-section of 19 children at the time of type 1 diabetes diagnosis and 16 healthy children were also analysed. EVs were isolated from cell culture media or serum using sequential ultracentrifugation or ExoQuick precipitation and EV miRNAs were assayed.
    Results: Cytokine treatment in beta cell lines and human islets resulted in a 1.5- to threefold increase in miR-21-5p. However, corresponding EVs were further enriched for this miRNA, with a three- to sixfold EV miR-21-5p increase in response to cytokine treatment. This difference was only partially reduced by pre-treatment of beta cells with Z-VAD-FMK to inhibit cytokine-induced caspase activity. Nanoparticle tracking analysis showed cytokines to have no effect on the number of EVs, implicating specific changes within EV cargo as being responsible for the increase in beta cell EV miR-21-5p. Sequential ultracentrifugation to separate EVs by size suggested that this effect was mostly due to cytokine-induced increases in exosome miR-21-5p. Longitudinal serum collections from NOD mice showed that EVs displayed progressive increases in miR-21-5p beginning 3 weeks prior to diabetes onset. To validate the relevance to human diabetes, we assayed serum from children with new-onset type 1 diabetes compared with healthy children. While total serum miR-21-5p and total serum EVs were reduced in diabetic participants, serum EV miR-21-5p was increased threefold compared with non-diabetic individuals. By contrast, both serum and EV miR-375-5p were increased in parallel among diabetic participants.
    Conclusions/interpretation: We propose that circulating EV miR-21-5p may be a promising marker of developing type 1 diabetes. Additionally, our findings highlight that, for certain miRNAs, total circulating miRNA levels are distinct from circulating EV miRNA content.
    MeSH term(s) Animals ; Apoptosis ; Biomarkers/metabolism ; Cytokines/metabolism ; Diabetes Mellitus, Type 1/metabolism ; Extracellular Vesicles ; Female ; Gene Expression Profiling ; Humans ; Inflammation ; Insulin-Secreting Cells/metabolism ; Interleukin-1beta/metabolism ; Mice ; Mice, Inbred NOD ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Biomarkers ; Cytokines ; Interleukin-1beta ; MIRN-21 microRNA, mouse ; MIRN21 microRNA, human ; MicroRNAs ; Tumor Necrosis Factor-alpha
    Language English
    Publishing date 2018-02-14
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1694-9
    ISSN 1432-0428 ; 0012-186X
    ISSN (online) 1432-0428
    ISSN 0012-186X
    DOI 10.1007/s00125-018-4559-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells.

    Sims, Emily K / Lakhter, Alexander J / Anderson-Baucum, Emily / Kono, Tatsuyoshi / Tong, Xin / Evans-Molina, Carmella

    Diabetologia

    2017  Volume 60, Issue 6, Page(s) 1057–1065

    Abstract: Aims/hypothesis: The role of beta cell microRNA (miR)-21 in the pathophysiology of type 1 diabetes has been controversial. Here, we sought to define the context of beta cell miR-21 upregulation in type 1 diabetes and the phenotype of beta cell miR-21 ... ...

    Abstract Aims/hypothesis: The role of beta cell microRNA (miR)-21 in the pathophysiology of type 1 diabetes has been controversial. Here, we sought to define the context of beta cell miR-21 upregulation in type 1 diabetes and the phenotype of beta cell miR-21 overexpression through target identification.
    Methods: Islets were isolated from NOD mice and mice treated with multiple low doses of streptozotocin, as a mouse model of diabetes. INS-1 832/13 beta cells and human islets were treated with IL-1β, IFN-γ and TNF-α to mimic the milieu of early type 1 diabetes. Cells and islets were transfected with miR-21 mimics or inhibitors. Luciferase assays and polyribosomal profiling (PRP) were performed to define miR-21-target interactions.
    Results: Beta cell miR-21 was increased in in vivo models of type 1 diabetes and cytokine-treated cells/islets. miR-21 overexpression decreased cell count and viability, and increased cleaved caspase 3 levels, suggesting increased cell death. In silico prediction tools identified the antiapoptotic mRNA BCL2 as a conserved miR-21 target. Consistent with this, miR-21 overexpression decreased BCL2 transcript and B cell lymphoma 2 (BCL2) protein production, while miR-21 inhibition increased BCL2 protein levels and reduced cleaved caspase 3 levels after cytokine treatment. miR-21-mediated cell death was abrogated in 828/33 cells, which constitutively overexpress Bcl2. Luciferase assays suggested a direct interaction between miR-21 and the BCL2 3' untranslated region. With miR-21 overexpression, PRP revealed a shift of the Bcl2 message towards monosome-associated fractions, indicating inhibition of Bcl2 translation. Finally, overexpression in dispersed human islets confirmed a reduction in BCL2 transcripts and increased cleaved caspase 3 production.
    Conclusions/interpretation: In contrast to the pro-survival role reported in other systems, our results demonstrate that miR-21 increases beta cell death via BCL2 transcript degradation and inhibition of BCL2 translation.
    MeSH term(s) Animals ; Diabetes Mellitus, Type 1/genetics ; Fluorescent Antibody Technique ; Humans ; Immunoblotting ; Insulin-Secreting Cells/metabolism ; Interferon-gamma/metabolism ; Interleukin-1beta/metabolism ; Male ; Mice ; Mice, Inbred NOD ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Interleukin-1beta ; MIRN21 microRNA, human ; MicroRNAs ; Proto-Oncogene Proteins c-bcl-2 ; Tumor Necrosis Factor-alpha ; mirn21 microRNA, rat ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2017-03-09
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 1694-9
    ISSN 1432-0428 ; 0012-186X
    ISSN (online) 1432-0428
    ISSN 0012-186X
    DOI 10.1007/s00125-017-4237-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2.

    Mani Shankar Babu / Sailendra Mahanta / Alexander J Lakhter / Takashi Hato / Subhankar Paul / Samisubbu R Naidu

    PLoS ONE, Vol 13, Iss 2, p e

    2018  Volume 0191419

    Abstract: Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for ... ...

    Abstract Reliance on aerobic glycolysis is one of the hallmarks of cancer. Although pyruvate kinase M2 (PKM2) is a key mediator of glycolysis in cancer cells, lack of selective agents that target PKM2 remains a challenge in exploiting metabolic pathways for cancer therapy. We report that unlike its structural analog shikonin, a known inhibitor of PKM2, lapachol failed to induce non-apoptotic cell death ferroxitosis in hypoxia. However, melanoma cells treated with lapachol showed a dose-dependent inhibition of glycolysis and a corresponding increase in oxygen consumption. Accordingly, in silico studies revealed a high affinity-binding pocket for lapachol on PKM2 structure. Lapachol inhibited PKM2 activity of purified enzyme as well as in melanoma cell extracts. Blockade of glycolysis by lapachol in melanoma cells led to decreased ATP levels and inhibition of cell proliferation. Furthermore, perturbation of glycolysis in melanoma cells with lapachol sensitized cells to mitochondrial protonophore and promoted apoptosis. These results present lapachol as an inhibitor of PKM2 to interrogate metabolic plasticity in tumor cells.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Impaired PIASy-Tip60 signaling weakens activation of p53 in melanoma.

    Lakhter, Alexander J / Kanginakudru, Sriramana / Warren, Simon / Touloukian, Christopher E / Boissy, Raymond E / Naidu, Samisubbu R

    Melanoma research

    2013  Volume 23, Issue 3, Page(s) 213–217

    Abstract: The tumor suppressor p53 plays a central role in preventing tumor development by promoting transcription of genes that stall cell cycle and induce cell death. Although the majority of melanomas express wild-type p53, the molecular mechanisms that impede ... ...

    Abstract The tumor suppressor p53 plays a central role in preventing tumor development by promoting transcription of genes that stall cell cycle and induce cell death. Although the majority of melanomas express wild-type p53, the molecular mechanisms that impede its activation remain unclear. We previously reported that the SUMO E3 ligase PIASy and the histone acetyltransferase Tip60 signaling cascade promote p53-dependent autophagy and apoptosis. We hypothesized that impairment in this signaling attenuates p53, thus disabling its apoptotic function in melanoma. Here, we show that human melanoma patient samples and cell lines maintain p53 expression but PIASy and/or Tip60 are frequently lost. We observed dysregulation of Tip60-mediated p53 transcription program in melanoma cell lines. Reconstitution of PIASy and Tip60 in melanoma cells increased genotoxic stress-induced apoptosis. Our study provides a clinical link of how sumoylation signaling may activate p53-mediated cell death in melanoma.
    MeSH term(s) Histone Acetyltransferases/genetics ; Histone Acetyltransferases/metabolism ; Humans ; Immunohistochemistry ; Lysine Acetyltransferase 5 ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Poly-ADP-Ribose Binding Proteins ; Protein Inhibitors of Activated STAT/genetics ; Protein Inhibitors of Activated STAT/metabolism ; Signal Transduction ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances PIAS4 protein, human ; Poly-ADP-Ribose Binding Proteins ; Protein Inhibitors of Activated STAT ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Histone Acetyltransferases (EC 2.3.1.48) ; KAT5 protein, human (EC 2.3.1.48) ; Lysine Acetyltransferase 5 (EC 2.3.1.48)
    Language English
    Publishing date 2013-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 1095779-0
    ISSN 1473-5636 ; 0960-8931
    ISSN (online) 1473-5636
    ISSN 0960-8931
    DOI 10.1097/CMR.0b013e328361056d
    Database MEDical Literature Analysis and Retrieval System OnLINE

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