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Role for Sphingosine Kinase 1 in Serine Deprivation

鞘氨醇激酶 1 在丝氨酸剥夺中的作用

基本信息

批准号：
10004160
负责人：
CUNGUI MAO
金额：
$ 30.45万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2022-08-31
项目状态：
已结题

项目摘要

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.

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)，癌症中的一种重要酶，作为丝氨酸的新的关键下游靶点并建立一种新的具有生物活性的鞘脂和SK1的非规范途径。作为一种潜在的丝氨酸传感器和效应器机制，对代谢重新编程至关重要。尽管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丝氨酸的外源来源，以促进最佳生长。重要的是，丝氨酸是由丝氨酸和棕榈酰Co-A缩合而成的鞘磷脂丝氨酸棕榈酰转移酶(SPT)。有趣的是，这种酶还可以利用丙氨酸作为底物，特别是在相对丝氨酸缺乏的情况下，这产生了小说，非规范的鞘磷脂1-脱氧鞘氨醇(DSA)。在最近令人兴奋的初步报告中研究发现，丝氨酸缺乏会导致DSA的积累，进而导致 SK1的丢失，从而启动代谢重新编程和适应的途径丝氨酸缺乏。这些研究提出了一些关于具体情况的基本问题丝氨酸剥夺对SK1调节的机制及丝氨酸剥夺对SK1调节的影响生物活性鞘脂网络：哪种特定的生物活性脂介导哪种特定的丝氨酸剥夺反应，以及其中涉及的生物学后果和机制是什么？至针对这些问题，我们提出了丝氨酸缺乏导致SK1丢失的假设在一种涉及DSA产生的新机制中。由此产生的SK的积累底物鞘氨醇调节适应性下游生物反应和代谢对路径进行重新编程。这一假设及其推论将通过以下方式进行调查以下具体目标：具体目标1.确定丝氨酸剥夺会导致SK1的丢失。特定目的2.确定介导的生物功能丝氨酸缺乏时SK1的丢失。具体目标3.确定SK1的作用癌细胞对丝氨酸剥夺反应的代谢重编程丢失和涉及的机制。确定丝氨酸剥夺调节SK1的机制生物活性鞘脂不仅将阐明这些令人兴奋的新联系这两条代谢途径，也将导致新的治疗方法的确定目标。