# Role for Sphingosine Kinase 1 in Serine Deprivation

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $304,547

## Abstract

The long-term goals of this project are to define the role and regulation of sphingosine kinase 1
(SK1), an important enzyme in cancer, as a novel and critical downstream target for serine
deprivation, and to establish a novel non-canonical pathway of bioactive sphingolipids and SK1
as a potential serine sensor and effector mechanism, critical for metabolic reprogramming.
Although serine is a non-essential amino acid, rapidly proliferating cancer cells also need an
exogenous source of serine for optimal growth. Importantly, serine is a direct precursor of
sphingolipids which are synthesized by the condensation of serine and palmitoyl Co-A by the
enzyme serine palmitoyl transferase (SPT). Intriguingly, this enzyme can also utilize alanine as
a substrate, especially in the context of relative serine deprivation, and this generates the novel,
non-canonical, sphingolipid 1-deoxysphinganine (dSa). In very recent and exciting preliminary
studies, we find that serine deprivation drives the accumulation of dSa, which in turn induces
loss of SK1, which then launches pathways of metabolic reprogramming and adaptation to
serine deprivation. These studies raise a number of fundamental questions as to the specific
mechanisms of serine deprivation on SK1 regulation, the effects of serine deprivation on the
networks of bioactive sphingolipids: which specific bioactive lipid mediates what specific serine
deprivation responses, and what are the biologic consequences and mechanisms involved? To
address these questions we propose the hypothesis that serine deprivation leads to SK1 loss
in a novel mechanism involving the generation of dSa. The resultant accumulation of the SK
substrate sphingosine regulates adaptive downstream biologic responses and metabolic
reprogramming pathways. This hypothesis and its corollaries will be investigated by pursuing
the following specific aims: Specific aim 1. To define the mechanisms by which serine
deprivation induces SK1 loss. Specific Aim 2. To determine the biologic functions mediated
by SK1 loss in response to serine deprivation. Specific Aim 3. To determine the role of SK1
loss in the metabolic reprogramming of cancer cells in response to serine deprivation and the
mechanisms involved. Identifying the mechanisms by which serine deprivation regulates SK1
and bioactive sphingolipids will not only shed light on these exciting novel connections between
these two metabolic pathways, but will also result in the identification of novel therapeutic
targets.

## Key facts

- **NIH application ID:** 10004160
- **Project number:** 5R01GM130878-03
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** CUNGUI MAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $304,547
- **Award type:** 5
- **Project period:** 2018-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004160

## Citation

> US National Institutes of Health, RePORTER application 10004160, Role for Sphingosine Kinase 1 in Serine Deprivation (5R01GM130878-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10004160. Licensed CC0.

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