Examining the effect of anti-tumor lipid drugs on pH homeostasis and membrane structure in Saccharomyces cerevisiae

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 effect 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.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Biological Sciences

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2013

Author dc:creator

• Czyz, Ola Aleksandra Joanna

Advisor dc:contributor.advisor

• Zaremberg, Vanina

• Biology--Cell
• Genetics

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/26025

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/700