Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
National Clinical Research Center for Cancer, Tianjin, China.
Cell Death Dis. 2024 Aug 6;15(8):567. doi: 10.1038/s41419-024-06961-7.
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 homoeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.
实体瘤在进展过程中常常会经历营养不足。肿瘤细胞如何适应时间和空间上的营养不足仍然不清楚。我们之前通过转录组筛选发现，STC2 是暴露于营养不足的细胞中上调最明显的基因之一，这表明 STC2 在细胞适应营养不足方面具有潜在作用。然而，STC2 诱导的分子机制以及随后的适应机制仍不清楚。在这里，我们报告说，在 Gln-/Glc-剥夺的情况下，STC2 蛋白的表达显著增加并分泌到培养基中。STC2 启动子包含顺式元件，这些元件可被 ATF4 和 p65/RelA（两种可被多种细胞应激激活的转录因子）激活。从生物学上讲，STC2 的诱导和分泌促进了细胞在营养不足时的存活，但减弱了细胞的增殖，从而使癌细胞的优先事项从增殖转变为存活。在小鼠异种移植中，缺失 STC2 会通过诱导细胞凋亡和坏死来损害肿瘤的生长。从机制上讲，在营养不足的情况下，细胞内的活性氧（ROS）水平增加，而缺乏 STC2 会进一步增加 ROS 水平，导致细胞凋亡增加。RNA-Seq 分析显示，STC2 的诱导抑制了单胺氧化酶 B（MAOB）的表达，MAOB 是一种产生 ROS 的线粒体膜酶。此外，还在人类肿瘤样本中发现了 STC2 诱导与 MAOB 水平之间的负相关关系。重要的是，在培养基中添加重组 STC2 可有效抑制 MAOB 的表达以及细胞凋亡，这表明 STC2 以自分泌/旁分泌的方式发挥作用。总之，我们的研究结果表明，营养不足会诱导 STC2 的表达，进而通过维持氧化还原平衡来控制肿瘤细胞对营养不足的适应，这突出了 STC2 作为癌症治疗的治疗靶点的潜力。
