Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk
Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk
复制标题
DOI：
10.1016/j.celrep.2019.11.079
复制
发表时间：
2019-12-17
期刊：
影响因子：
8.8
通讯作者：
Romero, Iris L.
中科院分区：
文献类型：
--
作者：
Hart, Peter C.;Kenny, Hilary A.;Romero, Iris L.
肿瘤微环境 (TME) 在癌症进展中发挥着关键作用，在卵巢癌 (OvCa) 中，主要的 TME 是大网膜。在这里，我们证明糖尿病药物二甲双胍会改变大网膜微环境中的间皮细胞。二甲双胍通过阻断 OvCa 细胞 TGF-β 信号传导以及间皮细胞产生 CCL2 和 IL-8 来中断肿瘤和间皮细胞之间的双向信号传导。二甲双胍对肿瘤间质串扰的抑制是由于三羧酸 (TCA) 酶琥珀酰辅酶 A 连接酶 (SUCLG2) 的表达减少所致。通过抑制这种 TCA 酶及其代谢物琥珀酸，二甲双胍激活脯氨酰羟化酶 (PHD)，导致间皮细胞中缺氧诱导因子 1 α (HIF1 α) 的降解。在器官型 3D 模型中，二甲双胍破坏间皮细胞中 HIF1 α 驱动的 IL-8 信号传导，导致 OvCa 侵袭减少。这些发现表明，二甲双胍可以靶向 TME 中间皮细胞和 OvCa 细胞之间的促肿瘤信号传导。
The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-beta signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1 alpha (HIF1 alpha) in mesothelial cells. Disruption of HIF1 alpha-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin.