The lysophosphatidylcholine analogue, edelfosine is a potent anti-tumor lipid drug that is known to target cellular membranes. The underlying mechanisms leading to cell death remain largely controversial, although previous results obtained using yeast, have indicated that edelfosine associates with lipid rafts at the plasma membrane (PM), resulting in the internalization of essential proton pump, Pma1 and ergosterol. To further elucidate the conditions that enhance or prevent the cytotoxic

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... t of edelfosine, genome-wide surveys in the model organism Saccharomyces cerevisiae were performed. The results of these screens indicated that maintenance of pH homeostasis modulates cell sensitivity to edelfosine. Our studies further demonstrated that edelfosine induces intracellular acidification and alters PM organization by selectively inducing ubiquitination and subsequent endocytosis of PM transporters. We also showed that the second-generation anti-tumor lipids, miltefosine and perifosine, cause PM disorganization in a manner analogous to edelfosine, suggesting a similar mode of action for this drug family.