Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen
Identifieur interne : 000535 ( Main/Exploration ); précédent : 000534; suivant : 000536Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen
Auteurs : Samy A. F. Morad [Égypte, États-Unis] ; Matthew R. Macdougall [États-Unis] ; Noha Abdelmageed [Égypte] ; Li-Pin Kao [États-Unis] ; David J. Feith [États-Unis] ; Su-Fern Tan [États-Unis] ; Mark Kester [États-Unis] ; Thomas P. Loughran [États-Unis] ; Hong-Gang Wang [États-Unis] ; Myles C. Cabot [États-Unis]Source :
- Experimental cell research [ 0014-4827 ] ; 2019.
Abstract
Acute myelogenous leukemia (AML) is a hematological malignancy marked by the accumulation of large numbers of immature myeloblasts in bone marrow. The overall prognosis in AML is poor; hence, there is a pressing need to improve treatment. Although the sphingolipid (SL) ceramide demonstrates known cancer suppressor properties, it’s mechanism of action is multifaceted. Our studies in leukemia and other cancers have demonstrated that when combined with the antiestrogen, tamoxifen, the apoptosis-inducting effect of ceramide is greatly enhanced. The goal of the present study was to establish whether a ceramide-tamoxifen regimen also affects autophagic-driven cellular responses in leukemia. Using the human AML cell line KG-1, we demonstrate that, unlike exposure to the single agents, combination C6-ceramide-tamoxifen upregulated LC3-II expression, inhibited the mTOR signaling pathway, and synergistically induced KG-1 cell death in an Atg5-dependent manner. In addition, colocalization of autophagosome and mitochondria, indicative of mitophagosome formation and mitophagy, was observed. Versatility of the drug regimen was confirmed by experiments in MV4–11 cells, a
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DOI: 10.1016/j.yexcr.2019.05.021
PubMed: 31112736
PubMed Central: 6909922
Affiliations:
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Cabot</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834</wicri:regionArea><wicri:noRegion>NC 27834</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31112736</idno><idno type="pmc">6909922</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909922</idno><idno type="RBID">PMC:6909922</idno><idno type="doi">10.1016/j.yexcr.2019.05.021</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000377</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000377</idno><idno type="wicri:Area/Pmc/Curation">000377</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000377</idno><idno type="wicri:Area/Pmc/Checkpoint">000488</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000488</idno><idno type="wicri:Area/Ncbi/Merge">000636</idno><idno type="wicri:Area/Ncbi/Curation">000636</idno><idno type="wicri:Area/Ncbi/Checkpoint">000636</idno><idno type="wicri:doubleKey">0014-4827:2019:Morad S:pivotal:role:of</idno><idno type="wicri:Area/Main/Merge">000535</idno><idno type="wicri:Area/Main/Curation">000535</idno><idno type="wicri:Area/Main/Exploration">000535</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen</title><author><name sortKey="Morad, Samy A F" sort="Morad, Samy A F" uniqKey="Morad S" first="Samy A. F." last="Morad">Samy A. F. Morad</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt</nlm:aff><country xml:lang="fr">Égypte</country><wicri:regionArea>Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523</wicri:regionArea><wicri:noRegion>83523</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834</wicri:regionArea><wicri:noRegion>NC 27834</wicri:noRegion></affiliation></author><author><name sortKey="Macdougall, Matthew R" sort="Macdougall, Matthew R" uniqKey="Macdougall M" first="Matthew R." last="Macdougall">Matthew R. Macdougall</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834</wicri:regionArea><wicri:noRegion>NC 27834</wicri:noRegion></affiliation></author><author><name sortKey="Abdelmageed, Noha" sort="Abdelmageed, Noha" uniqKey="Abdelmageed N" first="Noha" last="Abdelmageed">Noha Abdelmageed</name><affiliation wicri:level="1"><nlm:aff id="A3">Department of Pharmacology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt</nlm:aff><country xml:lang="fr">Égypte</country><wicri:regionArea>Department of Pharmacology, Faculty of Veterinary Medicine, Sohag University, Sohag</wicri:regionArea><wicri:noRegion>Sohag</wicri:noRegion></affiliation></author><author><name sortKey="Kao, Li Pin" sort="Kao, Li Pin" uniqKey="Kao L" first="Li-Pin" last="Kao">Li-Pin Kao</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834</wicri:regionArea><wicri:noRegion>NC 27834</wicri:noRegion></affiliation></author><author><name sortKey="Feith, David J" sort="Feith, David J" uniqKey="Feith D" first="David J." last="Feith">David J. Feith</name><affiliation wicri:level="1"><nlm:aff id="A4">University of Virginia Cancer Center, Charlottesville, VA, 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Virginia Cancer Center, Charlottesville, VA, 22908</wicri:regionArea><wicri:noRegion>22908</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA, 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA, 22908</wicri:regionArea><wicri:noRegion>22908</wicri:noRegion></affiliation></author><author><name sortKey="Tan, Su Fern" sort="Tan, Su Fern" uniqKey="Tan S" first="Su-Fern" last="Tan">Su-Fern Tan</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA, 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA, 22908</wicri:regionArea><wicri:noRegion>22908</wicri:noRegion></affiliation></author><author><name sortKey="Kester, Mark" sort="Kester, Mark" uniqKey="Kester M" first="Mark" last="Kester">Mark Kester</name><affiliation wicri:level="1"><nlm:aff id="A4">University of Virginia Cancer Center, Charlottesville, VA, 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Virginia Cancer Center, Charlottesville, VA, 22908</wicri:regionArea><wicri:noRegion>22908</wicri:noRegion></affiliation></author><author><name sortKey="Loughran, Thomas P" sort="Loughran, Thomas P" uniqKey="Loughran T" first="Thomas P." last="Loughran">Thomas P. Loughran</name><affiliation wicri:level="1"><nlm:aff id="A4">University of Virginia Cancer Center, Charlottesville, VA, 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Virginia Cancer Center, Charlottesville, VA, 22908</wicri:regionArea><wicri:noRegion>22908</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA, 22908, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Hematology/Oncology, University of Virginia, Charlottesville, VA, 22908</wicri:regionArea><wicri:noRegion>22908</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Hong Gang" sort="Wang, Hong Gang" uniqKey="Wang H" first="Hong-Gang" last="Wang">Hong-Gang Wang</name><affiliation wicri:level="1"><nlm:aff id="A6">Department of Pediatrics, Penn State Hersey College of Medicine, Hershey, PA, 17033, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Penn State Hersey College of Medicine, Hershey, PA, 17033</wicri:regionArea><wicri:noRegion>17033</wicri:noRegion></affiliation></author><author><name sortKey="Cabot, Myles C" sort="Cabot, Myles C" uniqKey="Cabot M" first="Myles C." last="Cabot">Myles C. Cabot</name><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, East Carolina University, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, Greenville, NC 27834</wicri:regionArea><wicri:noRegion>NC 27834</wicri:noRegion></affiliation></author></analytic><series><title level="j">Experimental cell research</title><idno type="ISSN">0014-4827</idno><idno type="eISSN">1090-2422</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Acute myelogenous leukemia (AML) is a hematological malignancy marked by the accumulation of large numbers of immature myeloblasts in bone marrow. The overall prognosis in AML is poor; hence, there is a pressing need to improve treatment. Although the sphingolipid (SL) ceramide demonstrates known cancer suppressor properties, it’s mechanism of action is multifaceted. Our studies in leukemia and other cancers have demonstrated that when combined with the antiestrogen, tamoxifen, the apoptosis-inducting effect of ceramide is greatly enhanced. The goal of the present study was to establish whether a ceramide-tamoxifen regimen also affects autophagic-driven cellular responses in leukemia. Using the human AML cell line KG-1, we demonstrate that, unlike exposure to the single agents, combination C6-ceramide-tamoxifen upregulated LC3-II expression, inhibited the mTOR signaling pathway, and synergistically induced KG-1 cell death in an Atg5-dependent manner. In addition, colocalization of autophagosome and mitochondria, indicative of mitophagosome formation and mitophagy, was observed. Versatility of the drug regimen was confirmed by experiments in MV4–11 cells, a <italic>FLT3-ITD</italic> AML mutant. These results indicate that the C6-ceramide-tamoxifen regimen plays a pivotal role inducing autophagy in AML, and thus constitutes a novel therapeutic design.</p></div></front></TEI><affiliations><list><country><li>Égypte</li><li>États-Unis</li></country></list><tree><country name="Égypte"><noRegion><name sortKey="Morad, Samy A F" sort="Morad, Samy A F" uniqKey="Morad S" first="Samy A. F." last="Morad">Samy A. F. Morad</name></noRegion><name sortKey="Abdelmageed, Noha" sort="Abdelmageed, Noha" uniqKey="Abdelmageed N" first="Noha" last="Abdelmageed">Noha Abdelmageed</name></country><country name="États-Unis"><noRegion><name sortKey="Morad, Samy A F" sort="Morad, Samy A F" uniqKey="Morad S" first="Samy A. F." last="Morad">Samy A. F. Morad</name></noRegion><name sortKey="Cabot, Myles C" sort="Cabot, Myles C" uniqKey="Cabot M" first="Myles C." last="Cabot">Myles C. Cabot</name><name sortKey="Feith, David J" sort="Feith, David J" uniqKey="Feith D" first="David J." last="Feith">David J. Feith</name><name sortKey="Feith, David J" sort="Feith, David J" uniqKey="Feith D" first="David J." last="Feith">David J. Feith</name><name sortKey="Kao, Li Pin" sort="Kao, Li Pin" uniqKey="Kao L" first="Li-Pin" last="Kao">Li-Pin Kao</name><name sortKey="Kester, Mark" sort="Kester, Mark" uniqKey="Kester M" first="Mark" last="Kester">Mark Kester</name><name sortKey="Loughran, Thomas P" sort="Loughran, Thomas P" uniqKey="Loughran T" first="Thomas P." last="Loughran">Thomas P. Loughran</name><name sortKey="Loughran, Thomas P" sort="Loughran, Thomas P" uniqKey="Loughran T" first="Thomas P." last="Loughran">Thomas P. Loughran</name><name sortKey="Macdougall, Matthew R" sort="Macdougall, Matthew R" uniqKey="Macdougall M" first="Matthew R." last="Macdougall">Matthew R. Macdougall</name><name sortKey="Tan, Su Fern" sort="Tan, Su Fern" uniqKey="Tan S" first="Su-Fern" last="Tan">Su-Fern Tan</name><name sortKey="Wang, Hong Gang" sort="Wang, Hong Gang" uniqKey="Wang H" first="Hong-Gang" last="Wang">Hong-Gang Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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