Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells

Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness of aneuploid cells. Remarkably, the fitness of aneuploid cells improves or deteriorates upon genetically decreasing or increasing ceramides, respectively. Combined targeting of serine and sphingolipid synthesis could be exploited to specifically target cancer cells, the vast majority of which are aneuploid. Hwang et al. demonstrate that aneuploid yeast cells rely on the synthesis of the amino acid serine for their viability. Serine is used for the synthesis of sphingolipids that control the fitness of aneuploid cells. Aneuploid cells are vulnerable to combined inhibition of serine and sphingolipid biosynthesis.

Original languageEnglish
Pages (from-to)3807-3818
Number of pages12
JournalCell Reports
Volume21
Issue number13
DOIs
StatePublished - Dec 26 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s)

Keywords

  • aneuploidy
  • ceramide
  • chromosomes
  • genomic istability
  • long-chain bases
  • metabolism
  • myriocin
  • serine
  • sphingolipids
  • sphingosine

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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