Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen

Samy A.F. Morad, Matthew R. MacDougall, Noha Abdelmageed, Li Pin Kao, David J. Feith, Su Fern Tan, Mark Kester, Thomas P. Loughran, Hong-Gang Wang, Myles C. Cabot

Research output: Contribution to journalArticle

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 FLT3-ITD 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.

Original languageEnglish (US)
Pages (from-to)256-264
Number of pages9
JournalExperimental Cell Research
Volume381
Issue number2
DOIs
StatePublished - Aug 15 2019

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Mitochondrial Degradation
Ceramides
Tamoxifen
Acute Myeloid Leukemia
Pharmaceutical Preparations
Leukemia
Granulocyte Precursor Cells
Sphingolipids
Estrogen Receptor Modulators
Autophagy
Hematologic Neoplasms
Neoplasms
Mitochondria
Cell Death
Bone Marrow
Apoptosis
Cell Line

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Morad, S. A. F., MacDougall, M. R., Abdelmageed, N., Kao, L. P., Feith, D. J., Tan, S. F., ... Cabot, M. C. (2019). Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen. Experimental Cell Research, 381(2), 256-264. https://doi.org/10.1016/j.yexcr.2019.05.021
Morad, Samy A.F. ; MacDougall, Matthew R. ; Abdelmageed, Noha ; Kao, Li Pin ; Feith, David J. ; Tan, Su Fern ; Kester, Mark ; Loughran, Thomas P. ; Wang, Hong-Gang ; Cabot, Myles C. / Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen. In: Experimental Cell Research. 2019 ; Vol. 381, No. 2. pp. 256-264.
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Morad, SAF, MacDougall, MR, Abdelmageed, N, Kao, LP, Feith, DJ, Tan, SF, Kester, M, Loughran, TP, Wang, H-G & Cabot, MC 2019, 'Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen', Experimental Cell Research, vol. 381, no. 2, pp. 256-264. https://doi.org/10.1016/j.yexcr.2019.05.021

Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen. / Morad, Samy A.F.; MacDougall, Matthew R.; Abdelmageed, Noha; Kao, Li Pin; Feith, David J.; Tan, Su Fern; Kester, Mark; Loughran, Thomas P.; Wang, Hong-Gang; Cabot, Myles C.

In: Experimental Cell Research, Vol. 381, No. 2, 15.08.2019, p. 256-264.

Research output: Contribution to journalArticle

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T1 - Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen

AU - Morad, Samy A.F.

AU - MacDougall, Matthew R.

AU - Abdelmageed, Noha

AU - Kao, Li Pin

AU - Feith, David J.

AU - Tan, Su Fern

AU - Kester, Mark

AU - Loughran, Thomas P.

AU - Wang, Hong-Gang

AU - Cabot, Myles C.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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 FLT3-ITD 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.

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