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 language | English (US) |
|---|---|
| Pages (from-to) | 256-264 |
| Number of pages | 9 |
| Journal | Experimental Cell Research |
| Volume | 381 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 15 2019 |
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All Science Journal Classification (ASJC) codes
- Cell Biology
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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 journal › Article
TY - JOUR
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065902411&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065902411&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2019.05.021
DO - 10.1016/j.yexcr.2019.05.021
M3 - Article
VL - 381
SP - 256
EP - 264
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 2
ER -