Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
The Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
FASEB J. 2021 Feb;35(2):e21284. doi: 10.1096/fj.202001814RR.
It has been well-established that cancer cells often display altered metabolic profiles, and recent work has concentrated on how cancer cells adapt to serine removal. Serine can be either taken exogenously or synthesized from glucose, and its regulation forms an important mechanism for nutrient integration. One of the several important metabolic roles for serine is in the generation of bioactive sphingolipids since it is the main substrate for serine palmitoyltransferase, the initial and rate-limiting enzyme in the synthesis of sphingolipids. Previously, serine deprivation has been connected to the action of the tumor suppressor p53, and we have previously published on a role for p53 regulating sphingosine kinase 1 (SK1), an enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). SK1 is a key enzyme in sphingolipid synthesis that functions in pro-survival and tumor-promoting pathways and whose expression is also often elevated in cancers. Here we show that SK1 was degraded during serine starvation in a time and dose-dependent manner, which led to sphingosine accumulation. This was independent of effects on p53 but required the action of the proteasome. Furthermore, we show that overexpression of SK1, to compensate for SK1 loss, was detrimental to cell growth under conditions of serine starvation, demonstrating that the suppression of SK1 under these conditions is adaptive. Mitochondrial oxygen consumption decreased in response to SK1 degradation, and this was accompanied by an increase in intracellular reactive oxygen species (ROS). Suppression of ROS with N-acteylcysteine resulted in suppression of the metabolic adaptations and in decreased cell growth under serine deprivation. The effects of SK1 suppression on ROS were mimicked by D-erythro-sphingosine, whereas S1P was ineffective, suggesting that the effects of loss of SK1 were due to the accumulation of its substrate sphingosine. This study reveals a new mechanism for regulating SK1 levels and a link of SK1 to serine starvation as well as mitochondrial function.
已经证实癌细胞通常表现出代谢特征的改变，最近的研究集中在癌细胞如何适应丝氨酸的去除。丝氨酸可以从外源性摄取或从葡萄糖合成，其调节形成了营养物质整合的重要机制。丝氨酸的几个重要代谢作用之一是产生生物活性鞘脂，因为它是丝氨酸棕榈酰转移酶的主要底物，丝氨酸棕榈酰转移酶是鞘脂合成的初始和限速酶。先前，丝氨酸剥夺与肿瘤抑制因子 p53 的作用有关，我们之前发表过关于 p53 调节鞘氨醇激酶 1（SK1）的作用的文章，该酶将鞘氨醇磷酸化为鞘氨醇-1-磷酸（S1P）。SK1 是鞘脂合成中的关键酶，在促生存和肿瘤促进途径中发挥作用，其表达在癌症中也经常升高。在这里，我们显示 SK1 在丝氨酸饥饿时以时间和剂量依赖的方式降解，导致鞘氨醇积累。这与 p53 的作用无关，但需要蛋白酶体的作用。此外，我们还表明，过表达 SK1 以补偿 SK1 的缺失，在丝氨酸饥饿条件下对细胞生长有害，表明在这些条件下抑制 SK1 是适应性的。线粒体耗氧量随 SK1 降解而降低，同时细胞内活性氧（ROS）增加。用 N-乙酰半胱氨酸抑制 ROS 导致代谢适应的抑制和丝氨酸剥夺下细胞生长的减少。ROS 的抑制作用与 D-erythro-鞘氨醇相似，而 S1P 无效，表明 SK1 缺失的影响是由于其底物鞘氨醇的积累。这项研究揭示了调节 SK1 水平的新机制以及 SK1 与丝氨酸饥饿以及线粒体功能的联系。
