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

Cancer cells can become dependent on exogenous serine, depletion of which results in slower growth and activation of a number 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 levels of its lipid substrate, sphingosine (Sph), which mediates several adaptive biological responses. However, the signaling molecules that regulate levels of SK1 and Sph in response to SG deprivation have yet to be defined. Here, we identify 1-deoxysphinganine (dSA), a non-canonical sphingoid base generated in the absence of serine from the alternative condensation of alanine and palmitoyl CoA by serine palmitoyl transferase (SPT), as a proximal mediator of SG deprivation in SK1 loss and Sph level elevation in SG deprivation in cancer cells. SG starvation markedly increased dSA levels in vitro and in vivo, and in turn induced SK1 degradation through a SPT-dependent mechanism, resulting in an increase in SPH levels. Addition of exogenous dSA caused a moderate increase in intracellular reactive oxygen species (ROS), which in turn decreased pyruvate kinase PKM2 activity while increasing phosphoglycerate dehydrogenase (PHGDH) 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' non-toxic function for dSA.