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.