Role for Sphingosine Kinase 1 in Serine Deprivation

这个项目的长期目标是确定鞘氨醇激酶1的作用和调节 (SK1)作为丝氨酸的一个新的和关键的下游靶点， 剥夺，并建立一个新的非经典途径的生物活性鞘脂和SK 1 作为潜在的丝氨酸传感器和效应器机制，对代谢重编程至关重要。 虽然丝氨酸是一种非必需氨基酸，但快速增殖的癌细胞也需要一种非必需氨基酸。 丝氨酸的外源性来源，用于最佳生长。重要的是，丝氨酸是一种直接的前体， 鞘脂，其通过丝氨酸和棕榈酰辅酶A的缩合合成， 丝氨酸棕榈酰转移酶（SPT）。有趣的是，这种酶也可以利用丙氨酸作为 底物，特别是在相对丝氨酸剥夺的情况下，这产生了新的， 非典型的鞘脂1-脱氧鞘氨醇（dSa）。在最近的一次激动人心的 研究中，我们发现，丝氨酸剥夺驱动dSa的积累，这反过来又诱导 SK 1的丢失，然后启动代谢重编程和适应的途径， 丝氨酸缺失这些研究提出了一些基本问题， 丝氨酸剥夺对SK 1调节的机制，丝氨酸剥夺对SK 1调节的影响， 生物活性鞘脂网络：哪种特定的生物活性脂质介导哪种特定的丝氨酸 剥夺反应，以及所涉及的生物后果和机制是什么？到 为了解决这些问题，我们提出了丝氨酸缺失导致SK 1丢失的假设 在一个新的机制，涉及产生dSa。由此产生的SK累积 底物鞘氨醇调节适应性下游生物反应和代谢 重新编程路径。这一假设及其推论将通过以下方式进行研究： 具体目标如下：具体目标1。为了确定丝氨酸 剥夺诱导SK 1损失。具体目标2。确定介导的生物学功能 SK 1的缺失导致了丝氨酸的缺失具体目标3。确定SK 1的作用 癌细胞对丝氨酸剥夺的代谢重编程的损失和 涉及的机制。确定丝氨酸剥夺调节SK 1的机制 和具有生物活性的鞘脂不仅将揭示这些令人兴奋的新的连接之间 这两种代谢途径，但也将导致识别新的治疗方法， 目标的

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.