Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.
Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.
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DOI：
10.1158/0008-5472.can-17-0015
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发表时间：
2017-08-15
期刊：
影响因子：
11.2
通讯作者：
Winter JM
中科院分区：
文献类型：
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作者：
Zarei M;Lal S;Parker SJ;Nevler A;Vaziri-Gohar A;Dukleska K;Mambelli-Lisboa NC;Moffat C;Blanco FF;Chand SN;Jimbo M;Cozzitorto JA;Jiang W;Yeo CJ;Londin ER;Seifert EL;Metallo CM;Brody JR;Winter JM
癌症侵袭性可能是由于缺乏营养的恶劣微环境的选择压力造成的。在这里，我们说明了这些条件如何促进胰腺导管腺癌（PDAC）的化疗耐药。葡萄糖或谷氨酰胺的戒断导致化疗5- 10倍的保护作用。与高血糖小鼠相比，低血糖小鼠的PDAC异种移植物对吉西他滨的敏感性较低。与这一观察结果一致，接受吉西他滨辅助治疗的患者（n = 107）血糖水平升高（糖化血红蛋白6.5%），生存率提高。我们发现，在这种情况下，增强的抗氧化防御是化学耐药的驱动因素。通过营养戒断或吉西他滨治疗，体外ROS水平增加一倍，但在吉西他滨治疗前剥夺PDAC细胞的营养会减弱这种效果。基于RNAi或CRISPR方法的机制研究表明，无论是否使用吉西他滨，RNA结合蛋白HuR在营养戒断下维持生存。值得注意的是，在hurr缺陷的PDAC细胞系中，RNA深度测序和功能分析发现，异柠檬酸脱氢酶1 （IDH1）是唯一受HuR调节的抗氧化酶。在免疫功能低下的小鼠中，hhr缺陷的PDAC细胞缺乏成功移植的能力，但IDH1在这些细胞中的过表达足以在低营养条件下完全恢复化疗耐药。总之，我们的研究结果强调了HuR-IDH1调控轴是胰腺癌的一个关键的、可操作的治疗靶点。
Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer.