Induction of programmed cell death (PCD) is a key cytotoxic effect of anticancer therapies. PCD is not confined to caspase-dependent apoptosis, but includes necroptosis, a regulated form of necrotic cell death controlled by Receptor-Interacting Protein (RIP) kinases 1 and 3, and Mixed Lineage Kinase Domain-Like (MLKL) pseudo-kinase. Necroptosis functions as a defense mechanism against oncogenic mutations and pathogens and can be induced by a variety of anticancer agents. However, the functional role and regulatory mechanisms of necroptosis in anticancer therapy are poorly understood. In this study, we found that RIP3-dependent but RIP1-independent necroptosis is engaged by 5-fluorouracil (5-FU) and other widely used antimetabolite drugs, and functions as a major mode of cell death in a subset of colorectal cancer (CRC) cells that express RIP3. We identified a novel 5-FU-induced necroptosis pathway involving p53-mediated induction of the BH3-only Bcl-2 family protein, p53 upregulated modulator of apoptosis (PUMA), which promotes cytosolic release of mitochondrial DNA and stimulates its sensor z-DNA-binding protein 1 (ZBP1) to activate RIP3. PUMA/RIP3-dependent necroptosis mediates the in vitro and in vivo antitumor effects of 5-FU and promotes a robust antitumor immune response. Our findings provide a rationale for stimulating necroptosis to enhance tumor cell killing and antitumor immune response leading to improved CRC treatments.

中文翻译：

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PUMA/RIP3通过坏死性凋亡和局部免疫激活介导结直肠癌化疗反应

诱导程序性细胞死亡（PCD）是抗癌疗法的关键细胞毒性作用。PCD 不仅限于 caspase 依赖性细胞凋亡，还包括坏死性凋亡，这是一种由受体相互作用蛋白 (RIP) 激酶 1 和 3 以及混合谱系激酶结构域样 (MLK​​L) 假激酶控制的坏死性细胞死亡的调节形式。坏死性凋亡是针对致癌突变和病原体的防御机制，可以由多种抗癌药物诱导。然而，人们对坏死性凋亡在抗癌治疗中的功能作用和调节机制知之甚少。在这项研究中，我们发现 RIP3 依赖性但不依赖 RIP1 的坏死性凋亡与 5-氟尿嘧啶 (5-FU) 和其他广泛使用的抗代谢药物有关，并且是结直肠癌 (CRC) 亚型中细胞死亡的主要模式。 ) 表达 RIP3 的细胞。我们发现了一种新的 5-FU 诱导的坏死性凋亡途径，涉及 p53 介导的 BH3-only Bcl-2 家族蛋白、p53 上调细胞凋亡调节剂 (PUMA) 的诱导，促进线粒体 DNA 的胞质释放并刺激其传感器 z-DNA -结合蛋白 1 (ZBP1) 激活 RIP3。PUMA/RIP3 依赖性坏死性凋亡介导 5-FU 的体外和体内抗肿瘤作用，并促进强大的抗肿瘤免疫反应。我们的研究结果为刺激坏死性凋亡以增强肿瘤细胞杀伤和抗肿瘤免疫反应从而改善结直肠癌治疗提供了理论基础。