Grabocka Elda, Bar-Sagi Dafna
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Cell. 2016 Dec 15;167(7):1803-1813.e12. doi: 10.1016/j.cell.2016.11.035.
There is growing evidence that stress-coping mechanisms represent tumor cell vulnerabilities that may function as therapeutically beneficial targets. Recent work has delineated an integrated stress adaptation mechanism that is characterized by the formation of cytoplasmic mRNA and protein foci, termed stress granules (SGs). Here, we demonstrate that SGs are markedly elevated in mutant KRAS cells following exposure to stress-inducing stimuli. The upregulation of SGs by mutant KRAS is dependent on the production of the signaling lipid molecule 15-deoxy-delta 12,14 prostaglandin J2 (15-d-PGJ2) and confers cytoprotection against stress stimuli and chemotherapeutic agents. The secretion of 15-d-PGJ2 by mutant KRAS cells is sufficient to enhance SG formation and stress resistance in cancer cells that are wild-type for KRAS. Our findings identify a mutant KRAS-dependent cell non-autonomous mechanism that may afford the establishment of a stress-resistant niche that encompasses different tumor subclones. These results should inform the design of strategies to eradicate tumor cell communities.
越来越多的证据表明，应激应对机制代表了肿瘤细胞的脆弱性，可能作为具有治疗益处的靶点发挥作用。最近的研究描绘了一种整合的应激适应机制，其特征是形成细胞质mRNA和蛋白质聚集体，称为应激颗粒（SGs）。在这里，我们证明，在暴露于应激诱导刺激后，突变型KRAS细胞中的SGs显著升高。突变型KRAS对SGs的上调依赖于信号脂质分子15-脱氧-Δ12,14-前列腺素J2（15-d-PGJ2）的产生，并赋予细胞对应激刺激和化疗药物的保护作用。突变型KRAS细胞分泌的15-d-PGJ2足以增强KRAS野生型癌细胞中的SG形成和应激抗性。我们的研究结果确定了一种依赖于突变型KRAS的细胞非自主机制，该机制可能有助于建立一个包含不同肿瘤亚克隆的抗应激生态位。这些结果应为根除肿瘤细胞群落的策略设计提供参考。
