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Using Yeast to Develop Anti‐Tumor Therapeutic Agents That Cause Liponecrotic Death of Cancer Cells by Remodeling Lipid Metabolism
Author(s) -
Titorenko Vladimir,
ArliaCiommo Anthony,
Leonov Anna,
Piano Amanda
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.885.2
Subject(s) - lipid metabolism , microbiology and biotechnology , yeast , lipid droplet , peroxisome , programmed cell death , biochemistry , cancer cell , biology , autophagy , saccharomyces cerevisiae , metabolism , endoplasmic reticulum , cell , chemistry , apoptosis , cancer , gene , genetics
We discovered a novel form of programmed cell death (PCD) called ʺliponecrosisʺ. It can be triggered by an exposure of the yeast Saccharomyces cerevisiae to exogenous palmitoleic acid (POA), a monounsaturated fatty acid. We revealed a molecular mechanism underlying liponecrotic PCD. It is initiated if bulk quantities of exogenously added POA are incorporated into phospholipids (PL) that amass in the endoplasmic reticulum membrane, mitochondrial membranes and the plasma membrane. This triggers a cascade of events committing yeast to liponecrotic PCD, which is executed via an autophagic degradation of various cellular organelles and macromolecules. Two pathways of lipid metabolism can protect yeast from liponecrosis by reducing the flow of POA into PL synthesis pathways; these pro‐survival pathways include POA oxidation within peroxisomes and POA incorporation into neutral lipids deposited in lipid droplets. Of note, the relative rates of all these pathways of lipid metabolism in rapidly proliferating yeast cells are known to be similar to those in cancer cells. Moreover, various small molecules have been identified by chemical‐genetic profiling in yeast as target‐specific inhibitors or activators of different reactions involved in these pathways. We discuss how some of these small molecules, added alone or in different combinations, can be used for such remodeling of various lipid metabolism pathways in proliferating yeast cells that makes these cells susceptible to liponecrotic PCD. We infer that such screens in yeast can be used to develop anti‐tumor therapeutic agents eliciting liponecrotic death of cancer cells via specific remodeling of certain lipid metabolism pathways. Supported by NSERC of Canada.