Identification of a Detoxification Requirement During De Novo Sphingolipid Biosynthesis in Cancer Cells
Authors
Spears, Meghan E.Faculty Advisor
Dohoon KimAcademic Program
Cancer BiologyUMass Chan Affiliations
Molecular, Cell and Cancer BiologyDocument Type
Doctoral DissertationPublication Date
2022-05-25Keywords
Cancer MetabolismToxic Metabolites
Sphingolipid Biology
Sphingolipid Synthesis
Detoxification Enzyme
ER Stress
Cancer Therapy
Cancer Biology
Metadata
Show full item recordAbstract
Sphingolipids are a class of lipid molecules that function both as structural membrane components and as bioactive signaling molecules. Sphingolipids can be produced de novo or salvaged and recycled. Despite the established roles of sphingolipids such as sphingosine 1-phosphate and ceramides in regulating signaling involved in pro- and anti-tumorigenic cellular processes, the role of the de novo sphingolipid biosynthesis pathway in cancer is unclear. The main objective of this thesis study was to determine whether there is an essential role for this pathway in cancer and whether its disruption can be a cancer-specific metabolic vulnerability. Here, we find that de novo sphingolipid synthesis through the rate-limiting enzyme serine palmitoyltransferase (SPT) is not required in cancer cells due to their salvage capacity. However, upregulation of SPT in cancer cells creates a requirement to detoxify its product, 3-ketodihydrosphingosine (3KDS), via the downstream enzyme 3-ketodihydrosphingosine reductase (KDSR). We demonstrate that KDSR is essential in cancer cells both in vitro and in vivo to restrain the levels of its substrate 3KDS, the accumulation of which can disrupt ER structure and function, resulting in proteotoxic stress and cell death. Our findings also reveal that KDSR is essential specifically in cancer cells and not normal cells and that upregulation of SPT in cancer may act as a biomarker for sensitivity to targeting KDSR. Altogether, this thesis study provides new insights into the role of KDSR in the de novo sphingolipid biosynthesis pathway in both cancer and ER homeostasis and demonstrates the potential to exploit this for therapeutic purposes in a cancer-specific manner.DOI
10.13028/pk56-5g16Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32403Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/pk56-5g16