牛磺酸,一种非蛋白质氨基酸和常用的营养补充剂,可以保护各种组织免受与DNA损伤化疗剂顺铂的作用相关的变性。牛磺酸是否以及如何保护人类卵巢癌(OC)细胞免受顺铂引起的DNA损伤尚不清楚。我们发现OC腹水衍生的细胞比细胞培养模型的OC含有更多的细胞内牛磺酸。在文化中,细胞内牛磺酸浓度升高至OC腹水细胞相关水平抑制了各种OC细胞系和患者来源的类器官的增殖,糖酵解减少,并诱导细胞免受顺铂的保护。牛磺酸细胞保护与顺铂反应的DNA损伤减少有关。RNA测序的组合,反相蛋白质阵列,活细胞显微镜,流式细胞术,生化验证实验为牛磺酸介导的突变型或野生型p53与DNA结合的诱导提供了证据,参与细胞周期负调节的p53效应子的激活(p21),和糖酵解(TIGAR)。矛盾的是,牛磺酸对细胞增殖的抑制与促有丝分裂信号转导的激活有关,包括ERK,mTOR,和主要DNA损伤敏感分子如DNAPK的mRNA表达增加,ATM和ATR。虽然抑制ERK或p53不干扰牛磺酸保护细胞免受顺铂的能力,用Torin2抑制mTOR,一种临床相关的抑制剂,也靶向DNAPK和ATM/ATR,破坏了牛磺酸的细胞保护。我们的研究暗示,细胞内牛磺酸的升高可以抑制细胞生长和代谢,并激活涉及mTOR和DNA损伤感应信号转导的细胞保护机制。
Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We found that OC ascites-derived cells contained significantly more intracellular taurine than cell culture-modeled OC. In culture, elevation of intracellular taurine concentration to OC ascites-cell-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse-phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant or wild-type p53 binding to DNA, activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine\'s suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage-sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine\'s ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine\'s cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth and metabolism, and activate cell protective mechanisms involving mTOR and DNA damage-sensing signal transduction.