Mason Joshua A, Cockfield Jordan A, Pape Daniel J, Meissner Hannah, Sokolowski Michael T, White Taylor C, Valentín López José C, Liu Juan, Liu Xiaojing, Martínez-Reyes Inmaculada, Chandel Navdeep S, Locasale Jason W, Schafer Zachary T
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Cell Rep. 2021 Mar 16;34(11):108821. doi: 10.1016/j.celrep.2021.108821.
Loss of integrin-mediated attachment to extracellular matrix (ECM) proteins can trigger a variety of cellular changes that affect cell viability. Foremost among these is the activation of anoikis, caspase-mediated cell death induced by ECM detachment. In addition, loss of ECM attachment causes profound alterations in cellular metabolism, which can lead to anoikis-independent cell death. Here, we describe a surprising role for serum and glucocorticoid kinase-1 (SGK1) in the promotion of energy production when cells are detached. Our data demonstrate that SGK1 activation is necessary and sufficient for ATP generation during ECM detachment and anchorage-independent growth. More specifically, SGK1 promotes a substantial elevation in glucose uptake because of elevated GLUT1 transcription. In addition, carbon flux into the pentose phosphate pathway (PPP) is necessary to accommodate elevated glucose uptake and PPP-mediated glyceraldehyde-3-phosphate (G3P) is necessary for ATP production. Thus, our data show SGK1 as master regulator of glucose metabolism and cell survival during ECM-detached conditions.
整合素介导的与细胞外基质（ECM）蛋白的附着丧失可引发多种影响细胞活力的细胞变化。其中最主要的是失巢凋亡的激活，即由ECM脱离诱导的半胱天冬酶介导的细胞死亡。此外，ECM附着丧失会导致细胞代谢发生深刻改变，这可能导致非失巢凋亡依赖性细胞死亡。在此，我们描述了血清和糖皮质激素激酶-1（SGK1）在细胞脱离时促进能量产生方面的一个惊人作用。我们的数据表明，SGK1激活对于ECM脱离和锚定非依赖性生长过程中的ATP生成是必要且充分的。更具体地说，由于GLUT1转录升高，SGK1促进葡萄糖摄取大幅增加。此外，进入磷酸戊糖途径（PPP）的碳通量对于适应升高的葡萄糖摄取是必要的，并且PPP介导的3-磷酸甘油醛（G3P）对于ATP产生是必要的。因此，我们的数据表明SGK1是ECM脱离条件下葡萄糖代谢和细胞存活的主要调节因子。
