PDF(Pubmed)
Abstract：
Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc-deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.
摘要：
实体肿瘤通常在进展过程中忍受营养不足。肿瘤细胞如何适应时间和空间营养不足尚不清楚。我们先前通过转录组筛选将STC2鉴定为暴露于营养不足的细胞中最上调的基因之一。表明STC2在细胞适应营养不足方面的潜力。然而,营养不足和随后的适应引起STC2诱导的分子机制仍然难以捉摸。这里,我们报道STC2蛋白显著增加并通过Gln-/Glc-剥夺分泌到培养基中。STC2启动子含有ATF4和p65/RelA激活的顺式元件，两种转录因子被多种细胞应激激活。生物学,STC2诱导和分泌促进细胞存活，但在营养不足时减弱细胞增殖，从而将癌细胞的优先级从增殖转变为存活。STC2的缺失通过诱导小鼠异种移植物中的细胞凋亡和坏死而损害肿瘤生长。机械上,在营养不足的条件下，细胞的活性氧（ROS）水平升高，STC2的缺乏进一步升高了导致细胞凋亡增加的ROS水平。RNA-Seq分析显示STC2诱导抑制单胺氧化酶B（MAOB）的表达，产生ROS的线粒体膜酶。此外，在人肿瘤样品中还鉴定出STC2和MAOB水平之间的负相关。重要的是,重组STC2对培养基的给药有效地抑制MAOB表达以及细胞凋亡，提示STC2以自分泌/旁分泌方式起作用。一起来看,我们的发现表明营养不足诱导STC2表达，反过来通过维持氧化还原稳态来控制癌细胞对营养不足的适应，强调STC2作为癌症治疗的治疗靶标的潜力。
