Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
J Clin Invest. 2021 Jan 4;131(1). doi: 10.1172/JCI137186.
Therapeutic strategies designed to target TP53-deficient cancer cells remain elusive. Here, we showed that TP53 loss initiated a pharmacologically actionable secretory process that drove lung adenocarcinoma (LUAD) progression. Molecular, biochemical, and cell biological studies showed that TP53 loss increased the expression of Golgi reassembly and stacking protein 55 kDa (G55), a Golgi stacking protein that maintains Golgi organelle integrity and is part of a GOLGIN45 (G45)-myosin IIA-containing protein complex that activates secretory vesicle biogenesis in the Golgi. TP53 loss activated G55-dependent secretion by relieving G55 and myosin IIA from miR-34a-dependent silencing. G55-dependent secreted proteins enhanced the proliferative and invasive activities of TP53-deficient LUAD cells and promoted angiogenesis and CD8+ T cell exhaustion in the tumor microenvironment. A small molecule that blocks G55-G45 interactions impaired secretion and reduced TP53-deficient LUAD growth and metastasis. These results identified a targetable secretory vulnerability in TP53-deficient LUAD cells.
针对 TP53 缺陷型癌细胞的治疗策略仍然难以捉摸。在这里，我们表明 TP53 缺失启动了一种可通过药理学手段靶向的分泌过程，从而推动肺腺癌（LUAD）的进展。分子、生化和细胞生物学研究表明，TP53 缺失增加了高尔基体再组装和堆积蛋白 55kDa（G55）的表达，G55 是一种高尔基体堆积蛋白，维持高尔基体细胞器的完整性，是含有 GOLGIN45（G45）-肌球蛋白 IIA 的蛋白复合物的一部分，该复合物在高尔基体中激活分泌小泡的生物发生。TP53 缺失通过解除 miR-34a 依赖性沉默，激活 G55 依赖性分泌，从而激活 G55 依赖性分泌。G55 依赖性分泌的蛋白质增强了 TP53 缺陷型 LUAD 细胞的增殖和侵袭活性，并促进了肿瘤微环境中的血管生成和 CD8+T 细胞耗竭。一种阻断 G55-G45 相互作用的小分子会损害分泌，并减少 TP53 缺陷型 LUAD 的生长和转移。这些结果确定了 TP53 缺陷型 LUAD 细胞中可靶向的分泌脆弱性。
