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A functional genomic screen in Saccharomyces cerevisiae reveals divergent mechanisms of resistance to different alkylphosphocholine chemotherapeutic agents

View ORCID ProfileJacquelin M. Garcia, Michael J. Schwabe, View ORCID ProfileDennis R. Voelker, View ORCID ProfileWayne R. Riekhof
doi: https://doi.org/10.1101/2020.10.16.343244
Jacquelin M. Garcia
*School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USA
3Division of Biology and Biomedical Sciences, Washington University, St. Louis, MO, USA
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Michael J. Schwabe
*School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USA
4Department of Surgery, Creighton University School of Medicine, Omaha, NE, USA
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Dennis R. Voelker
†Department of Medicine, National Jewish Health, Denver, CO, USA
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Wayne R. Riekhof
*School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USA
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  • For correspondence: wriekhof2@unl.edu
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Abstract

The alkylphosphocholine (APC) class of antineoplastic and antiprotozoal drugs, such as edelfosine and miltefosine, are structural mimics of lyso-phosphatidylcholine (lyso-PC), and are inhibitory to the yeast Saccharomyces cerevisiae at low micromolar concentrations. Cytotoxic effects related to inhibition of phospholipid synthesis, induction of an unfolded protein response, inhibition of oxidative phosphorylation, and disruption of lipid rafts have been attributed to members of this drug class, however the molecular mechanisms of action of these drugs remain incompletely understood. Cytostatic and cytotoxic effects of the alkylphosphocholines exhibit variability with regard to chemical structure, leading to differences in effectiveness against different organisms or cell types. We now report the comprehensive identification of Saccharomyces cerevisiae titratable-essential gene and haploid non-essential gene deletion mutants that are resistant to the APC drug miltefosine (hexadecyl-O-phosphocholine). 58 strains out of ~5600 tested displayed robust and reproducible resistance to miltefosine. This gene set was heavily enriched in functions associated with vesicular transport steps, especially those involving endocytosis and retrograde transport of endosome derived vesicles to the Golgi or vacuole, suggesting a role for these trafficking pathways in transport of miltefosine to potential sites of action in the endoplasmic reticulum (ER) and mitochondrion. In addition, we identified mutants with defects in phosphatidylinositol-4-phosphate synthesis (TetO::STT4) and hydrolysis (sac1Δ), an oxysterol binding protein homolog (osh2Δ), a number of ER resident proteins, and multiple components of the eisosome. These findings suggest that ER-plasma membrane contact sites and retrograde vesicle transport are involved in the interorganelle transport of lyso-PtdCho and related lyso-phospholipid-like analogs to their intracellular sites of cytotoxic activity.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 17, 2020.
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A functional genomic screen in Saccharomyces cerevisiae reveals divergent mechanisms of resistance to different alkylphosphocholine chemotherapeutic agents
Jacquelin M. Garcia, Michael J. Schwabe, Dennis R. Voelker, Wayne R. Riekhof
bioRxiv 2020.10.16.343244; doi: https://doi.org/10.1101/2020.10.16.343244
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A functional genomic screen in Saccharomyces cerevisiae reveals divergent mechanisms of resistance to different alkylphosphocholine chemotherapeutic agents
Jacquelin M. Garcia, Michael J. Schwabe, Dennis R. Voelker, Wayne R. Riekhof
bioRxiv 2020.10.16.343244; doi: https://doi.org/10.1101/2020.10.16.343244

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