1-Deoxysphinganine initiates adaptive responses to serine and glycine starvation in cancer cells via proteolysis of sphingosine kinase

Jean Philip Truman, Christian F. Ruiz, Emily Montal, Monica Garcia-Barros, Izolda Mileva, Ashley J. Snider, Yusuf A. Hannun, Lina M. Obeid, Cungui Mao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cancer cells may depend on exogenous serine, depletion of which results in slower growth and activation of adaptive metabolic changes. We previously demonstrated that serine and glycine (SG) deprivation causes loss of sphingosine kinase 1 (SK1) in cancer cells, thereby increasing the levels of its lipid substrate, sphingosine (Sph), which mediates several adaptive biological responses. However, the signaling molecules regulating SK1 and Sph levels in response to SG deprivation have yet to be defined. Here, we identify 1-deoxysphinganine (dSA), a noncanonical sphingoid base generated in the absence of serine from the alternative condensation of alanine and palmitoyl CoA by serine palmitoyl transferase, as a proximal mediator of SG deprivation in SK1 loss and Sph level elevation upon SG deprivation in cancer cells. SG starvation increased dSA levels in vitro and in vivo and in turn induced SK1 degradation through a serine palmitoyl transferase-dependent mechanism, thereby increasing Sph levels. Addition of exogenous dSA caused a moderate increase in intracellular reactive oxygen species, which in turn decreased pyruvate kinase PKM2 activity while increasing phosphoglycerate dehydrogenase levels, and thereby promoted serine synthesis. We further showed that increased dSA induces the adaptive cellular and metabolic functions in the response of cells to decreased availability of serine likely by increasing Sph levels. Thus, we conclude that dSA functions as an initial sensor of serine loss, SK1 functions as its direct target, and Sph functions as a downstream effector of cellular and metabolic adaptations. These studies define a previously unrecognized "physiological"nontoxic function for dSA.

Original languageEnglish (US)
Article number100154
JournalJournal of Lipid Research
Volume63
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • Hereditary sensory and autonomic neuropathy (HSAN)
  • Mass spectrometry
  • Phosphoglycerate dehydrogenase (PHGDH)
  • Pyruvate kinase (PKM2)
  • Reactive oxygen species (ROS)
  • Serine biosynthesis
  • Serine palmitoyl transferase (SPT)
  • Sphingosine
  • Sphingosine kinase
  • Ubiquitination

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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