Alexander Eric T, Fahey Erin, Phanstiel Otto, Gilmour Susan K
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
Department of Medical Education, College of Medicine, University of Central Florida, Biomolecular Research Annex, 12722 Research Parkway, Orlando, FL 32826, USA.
Biomedicines. 2023 Oct 5;11(10):2703. doi: 10.3390/biomedicines11102703.
GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival and progression. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine activates GCN2, thus rewiring metabolism to support tumor cell survival and drive myeloid immunosuppressive function. We sought to determine if the anti-tumor efficacy of a polyamine blocking therapy (PBT) may be mediated by its effect on GCN2. Unlike wild-type mice, PBT treatment in GCN2 knockout mice bearing syngeneic B16.F10 or EG7 tumors resulted in no tumor growth inhibition and no changes in the profile of infiltrating tumor immune cells. Studies with murine bone marrow cell cultures showed that increased polyamine metabolism and subsequent arginine depletion and GCN2 activation played an essential role in the generation and cytoprotective autophagy of myeloid derived suppressor cells (MDSCs) as well as the M2 polarization and survival of macrophages, all of which were inhibited by PBT. In all, our data suggest that polyamine-dependent GCN2 signaling in stromal cells promotes tumor growth and the development of the immunosuppressive tumor microenvironment, and that the PBT anti-tumor effect is mediated, at least in part, by targeting GCN2.
GCN2是氨基酸饥饿应激的主要传感器之一，其在应激性肿瘤微环境中的激活在肿瘤存活和进展中起关键作用。我们假设多胺生物合成增加以及随后前体精氨酸的消耗会激活GCN2，从而重新调整代谢以支持肿瘤细胞存活并驱动髓系免疫抑制功能。我们试图确定多胺阻断疗法（PBT）的抗肿瘤疗效是否可能由其对GCN2的作用介导。与野生型小鼠不同，在携带同基因B16.F10或EG7肿瘤的GCN2基因敲除小鼠中进行PBT治疗不会导致肿瘤生长抑制，也不会改变浸润性肿瘤免疫细胞的谱。对小鼠骨髓细胞培养物的研究表明，多胺代谢增加以及随后的精氨酸消耗和GCN2激活在髓系来源的抑制细胞（MDSC）的产生和细胞保护性自噬以及巨噬细胞的M2极化和存活中起重要作用，所有这些都被PBT抑制。总之，我们的数据表明，基质细胞中多胺依赖性GCN2信号传导促进肿瘤生长和免疫抑制性肿瘤微环境的发展，并且PBT的抗肿瘤作用至少部分是通过靶向GCN2介导的。
