Lipid droplets can promote drug accumulation and activation

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Stanford University
  • Genentech Incorporated

Details

Original languageEnglish (US)
Pages (from-to)206-213
Number of pages8
JournalNature chemical biology
Volume16
Issue number2
StatusPublished - Feb 1 2020
Peer-reviewedYes

Abstract

Genetic screens in cultured human cells represent a powerful unbiased strategy to identify cellular pathways that determine drug efficacy, providing critical information for clinical development. We used insertional mutagenesis-based screens in haploid cells to identify genes required for the sensitivity to lasonolide A (LasA), a macrolide derived from a marine sponge that kills certain types of cancer cells at low nanomolar concentrations. Our screens converged on a single gene, LDAH, encoding a member of the metabolite serine hydrolase family that is localized on the surface of lipid droplets. Mechanistic studies revealed that LasA accumulates in lipid droplets, where it is cleaved into a toxic metabolite by LDAH. We suggest that selective partitioning of hydrophobic drugs into the oil phase of lipid droplets can influence their activation and eventual toxicity to cells.

Citation formats

APA

Dubey, R., Stivala, C. E., Nguyen, H. Q., Goo, Y. H., Paul, A., Carette, J. E., ... Rohatgi, R. (2020). Lipid droplets can promote drug accumulation and activation. Nature chemical biology, 16(2), 206-213. https://doi.org/10.1038/s41589-019-0447-7

Harvard

Dubey, R, Stivala, CE, Nguyen, HQ, Goo, YH, Paul, A, Carette, JE, Trost, BM & Rohatgi, R 2020, 'Lipid droplets can promote drug accumulation and activation', Nature chemical biology, vol. 16, no. 2, pp. 206-213. https://doi.org/10.1038/s41589-019-0447-7