Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia
Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-04-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523318303863 |
| _version_ | 1818935285971419136 |
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| author | Naxin Guo Mitra Azadniv Myra Coppage Mary Nemer Jason Mendler Michael Becker Jane Liesveld |
| author_facet | Naxin Guo Mitra Azadniv Myra Coppage Mary Nemer Jason Mendler Michael Becker Jane Liesveld |
| author_sort | Naxin Guo |
| collection | DOAJ |
| description | Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of these two pathways remains unclear. Here we evaluated the effects of pevonedistat, an inhibitor of the NEDD8 activating enzyme (NAE), and sapanisertib (TAK-228), an inhibitor of mTORC1 and mTORC2 as single agents or in combination on AML cell lines. We found that inhibition of neddylation with pevonedistat partially inhibited mTOR signaling transduction and vice versa, inhibition of mTOR signaling with sapanisertib partially inhibited neddylation in AML cell lines. Pevonedistat alone was able to induce cytotoxicity in most AML cell lines as well as in primary AML, whereas sapanisertib alone decreased cell metabolic activity, reduced cell size and arrested cells in G0 phase with only minimal induction of cell death. In addition, pevonedistat was able to induce cell differentiation, arrest cells in G2/M cell cycle phases, and induce DNA re-replication and damage. However, co-treatment with sapanisertib suppressed pevonedistat induced apoptosis, differentiation, S/G2/M arrest, and DNA damage. Taken together, our data demonstrate that pevonedistat and sapanisertib exhibit distinct anti-tumor effects on AML cells, i.e. cytotoxic and cytostatic effects, respectively; however, sapanisertib can attenuate pevonedistat-induced cellular responses in AML cells. Understanding mTOR and neddylation pathway interaction could provide therapeutic strategies for treatment of AML and other malignancies. |
| first_indexed | 2024-12-20T05:17:45Z |
| format | Article |
| id | doaj.art-46299d77486349f28f6c368d36214d8e |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-20T05:17:45Z |
| publishDate | 2019-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-46299d77486349f28f6c368d36214d8e2022-12-21T19:52:07ZengElsevierTranslational Oncology1936-52332019-04-01124602613Effects of Neddylation and mTOR Inhibition in Acute Myelogenous LeukemiaNaxin Guo0Mitra Azadniv1Myra Coppage2Mary Nemer3Jason Mendler4Michael Becker5Jane Liesveld6Wilmot Cancer Institute, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642Wilmot Cancer Institute, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642Wilmot Cancer Institute, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642Wilmot Cancer Institute, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642; Department of Medicine, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642Wilmot Cancer Institute, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642; Department of Medicine, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642Wilmot Cancer Institute, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642; Department of Medicine, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642; Address all correspondence to: Jane L. Liesveld, MD, Department of Medicine, Hematology/Oncology, Box 704, University of Rochester school of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642-8609.Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of these two pathways remains unclear. Here we evaluated the effects of pevonedistat, an inhibitor of the NEDD8 activating enzyme (NAE), and sapanisertib (TAK-228), an inhibitor of mTORC1 and mTORC2 as single agents or in combination on AML cell lines. We found that inhibition of neddylation with pevonedistat partially inhibited mTOR signaling transduction and vice versa, inhibition of mTOR signaling with sapanisertib partially inhibited neddylation in AML cell lines. Pevonedistat alone was able to induce cytotoxicity in most AML cell lines as well as in primary AML, whereas sapanisertib alone decreased cell metabolic activity, reduced cell size and arrested cells in G0 phase with only minimal induction of cell death. In addition, pevonedistat was able to induce cell differentiation, arrest cells in G2/M cell cycle phases, and induce DNA re-replication and damage. However, co-treatment with sapanisertib suppressed pevonedistat induced apoptosis, differentiation, S/G2/M arrest, and DNA damage. Taken together, our data demonstrate that pevonedistat and sapanisertib exhibit distinct anti-tumor effects on AML cells, i.e. cytotoxic and cytostatic effects, respectively; however, sapanisertib can attenuate pevonedistat-induced cellular responses in AML cells. Understanding mTOR and neddylation pathway interaction could provide therapeutic strategies for treatment of AML and other malignancies.http://www.sciencedirect.com/science/article/pii/S1936523318303863 |
| spellingShingle | Naxin Guo Mitra Azadniv Myra Coppage Mary Nemer Jason Mendler Michael Becker Jane Liesveld Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia Translational Oncology |
| title | Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia |
| title_full | Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia |
| title_fullStr | Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia |
| title_full_unstemmed | Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia |
| title_short | Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia |
| title_sort | effects of neddylation and mtor inhibition in acute myelogenous leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S1936523318303863 |
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