Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine

Abstract

The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apoptosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cytochrome c release and the triggering of cell death. The overexpression of Bcl-2 or Bcl-xL blocks edelfosine-induced apoptosis. Edelfosine induces the redistribution of lipid rafts from the plasma membrane to the mitochondria. The pro-apoptotic action of edelfosine on cancer cells is associated with the recruitment of F1FO–ATP synthase into cholesterol-rich lipid rafts. Specific inhibition of the FO sector of the F1FO–ATP synthase, which contains the membrane-embedded c-subunit ring that constitutes the mitochondrial permeability transcription pore, hinders edelfosine-induced cell death. Taking together, the evidence shown here suggests that the ether lipid edelfosine could modulate cell death in cancer cells by direct interaction with mitochondria, and the reorganization of raft-located mitochondrial proteins that critically modulate cell death or survival. Here, we summarize and discuss the involvement of mitochondria in the antitumor action of the ether lipid edelfosine, pointing out the mitochondrial targeting of this drug as a major therapeutic approach, which can be extrapolated to other alkylphospholipid analogs. We also discuss the involvement of cholesterol transport and cholesterol-rich lipid rafts in the interactions between the organelles as well as in the role of mitochondria in the regulation of apoptosis in cancer cells and cancer therapy.

Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition

“…This could be due to the fact that the induction of apoptosis would require the involvement of additional processes that need time to be triggered and completed, probably to exceed a certain drug concentration threshold in the subcellular organelle to initiate the next proapoptotic signaling, and/or the onset of a series of events that, once initiated in the ER, should be transmitted to mitochondria and other subcellular organelles before the eventual manifestation of the apoptotic response. In this regard, we previously found that edelfosine-induced apoptosis involves ER, mitochondria and intracellular trafficking to promote cell death [ 1 , 29 , 31 , 63 , 81 , 82 ], and there is a kind of connection between these processes [ 47 , 63 , 83 ] for the onset of cell death.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…CL has been observed to enhance the formation of ion-permeable pore structures with channel-like properties by α-syn oligomers in lipid membranes [ 288 ]. MAMs, IMM, and OMM, with their lipid raft-like domains enriched with CL, easily form pores large enough to allow the transit of water and other small molecules that could cause mitochondrial swelling and Cyt c release [ 288 , 289 , 290 ]. Intriguingly, most ion channels preferentially reside in membrane raft-like microdomains [ 291 ].…”

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

“…The ER and the mitochondria interact through dynamic platforms known as mitochondria-associated membranes (MAMs) [224][225][226], which show higher levels of cholesterol compared to the rest of the ER [227,228], and provide an excellent scaffold for crosstalk and the transfer of lipids between the ER and the mitochondria [226,229,230]. Because edelfosine accumulates in lipid rafts [150,170,180,181,184,187,188,193,201,228], shows a high affinity for cholesterol [193,228,[231][232][233], and is also able to target the mitochondria [176,210,228]-likely through the involvement of lipid rafts [210,228]-it could be envisaged a network of central subcellular organelles involved in cell demise regulation that could be mediated by lipid rafts. In this context, edelfosine represents an excellent tool to unveil this raft-mediated membrane-ER-mitochondria network that could modulate signaling processes and cell fate.…”