Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 16; pp. 4460 - 4471
• Main Authors: Zarei, Mahsa, Lal, Shruti, Parker, Seth J, Nevler, Avinoam, Vaziri-Gohar, Ali, Dukleska, Katerina, Mambelli-Lisboa, Nicole C, Moffat, Cynthia, Blanco, Fernando F, Chand, Saswati N, Jimbo, Masaya, Cozzitorto, Joseph A, Jiang, Wei, Yeo, Charles J, Londin, Eric R, Seifert, Erin L, Metallo, Christian M, Brody, Jonathan R, Winter, Jordan M
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15-08-2017
• Subjects: Adenocarcinoma; Animals; Antioxidants; Cell Line, Tumor; Cell lines; Cell Proliferation - physiology; Chemoresistance; Chemotherapy; Cohort Studies; CRISPR; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Drug Resistance, Neoplasm; ELAV-Like Protein 1 - genetics; ELAV-Like Protein 1 - metabolism; Gemcitabine; Glucose; Glutamine; Humans; HuR protein; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Mice; Mice, Nude; Nutrients; Organoplatinum Compounds - pharmacology; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phenotype; Post-transcription; Protein Processing, Post-Translational; Reactive oxygen species; Ribonucleic acid; RNA; RNA-binding protein; RNA-mediated interference; Survival Analysis; Transcriptional Activation; Transfection; Up-Regulation; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-0015

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 (
= 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
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.
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