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

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.

• Authors: Samy A F Morad, Matthew R MacDougall, Noha Abdelmageed, Li-Pin Kao, David J Feith, Su-Fern Tan, Mark Kester, Thomas P Loughran Jr, Hong-Gang Wang, Myles C Cabot
• Journal: Experimental cell research (Exp Cell Res) Vol. 381 Issue 2 Pg. 256-264 (08 15 2019) ISSN: 1090-2422 [Electronic] United States
• PMID: 31112736 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• ATG5 protein, human
• Autophagy-Related Protein 5
• Ceramides
• Tamoxifen

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Autophagy-Related Protein 5 (physiology)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Ceramides (administration & dosage)
• Drug Synergism
• Humans
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Mitophagy (drug effects, physiology)
• Signal Transduction (drug effects)
• Tamoxifen (administration & dosage)
• Tumor Cells, Cultured