Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Sci Transl Med. 2018 Feb 7;10(427). doi: 10.1126/scitranslmed.aam7610.
The gastrointestinal (GI) epithelium is the fastest renewing adult tissue and is maintained by tissue-specific stem cells. Treatment-induced GI side effects are a major dose-limiting factor for chemotherapy and abdominal radiotherapy and can decrease the quality of life in cancer patients and survivors. p53 is a key regulator of the DNA damage response, and its activation results in stimulus- and cell type-specific outcomes via distinct effectors. We demonstrate that p53-dependent PUMA induction mediates chemotherapy-induced intestinal injury in mice. Genetic ablation of , but not of , protects against chemotherapy-induced lethal GI injury. Blocking chemotherapy-induced loss of LGR5 stem cells by KO or a small-molecule PUMA inhibitor (PUMAi) prevents perturbation of the stem cell niche, rapid activation of WNT and NOTCH signaling, and stem cell exhaustion during repeated exposures. PUMAi also protects human and mouse colonic organoids against chemotherapy-induced apoptosis and damage but does not protect cancer cells in vitro or in vivo. Therefore, targeting PUMA is a promising strategy for normal intestinal chemoprotection because it selectively blocks p53-dependent stem cell loss but leaves p53-dependent protective effects intact.
胃肠道（GI）上皮是成人组织中更新最快的组织，由组织特异性干细胞维持。治疗引起的胃肠道副作用是化疗和腹部放疗的主要剂量限制因素，会降低癌症患者和幸存者的生活质量。p53 是 DNA 损伤反应的关键调节因子，其激活通过不同的效应物导致刺激和细胞类型特异性的结果。我们证明，p53 依赖性 PUMA 诱导介导了小鼠化疗引起的肠道损伤。 但不是 的遗传缺失可防止化疗引起的致命胃肠道损伤。通过 KO 或小分子 PUMA 抑制剂（PUMAi）阻断化疗诱导的 LGR5 干细胞丢失，可防止干细胞龛位的破坏、WNT 和 NOTCH 信号的快速激活以及重复暴露期间干细胞耗竭。PUMAi 还可防止人源和鼠源结肠类器官发生化疗诱导的细胞凋亡和损伤，但在体外或体内均不能保护癌细胞。因此，靶向 PUMA 是一种有前途的正常肠道化学保护策略，因为它选择性地阻断 p53 依赖性干细胞丢失，但保留 p53 依赖性保护作用。
