دورية أكاديمية
Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.
| العنوان: | Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells. |
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| المؤلفون: | Zarei M; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Lal S; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Parker SJ; Department of Bioengineering, University of California, San Diego, La Jolla, California., Nevler A; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Vaziri-Gohar A; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Dukleska K; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Mambelli-Lisboa NC; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Moffat C; MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania., Blanco FF; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Chand SN; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Jimbo M; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Cozzitorto JA; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Jiang W; Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania., Yeo CJ; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Londin ER; Computational Medicine Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Seifert EL; MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.; Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania., Metallo CM; Moores Cancer Center, University of California, San Diego, La Jolla, California., Brody JR; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Winter JM; Department of Surgery, Division of Surgical Research, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. jordan.winter@jefferson.edu. |
| المصدر: | Cancer research [Cancer Res] 2017 Aug 15; Vol. 77 (16), pp. 4460-4471. Date of Electronic Publication: 2017 Jun 26. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | ELAV-Like Protein 1/*metabolism , Isocitrate Dehydrogenase/*metabolism , Pancreatic Neoplasms/*metabolism, Animals ; Cell Line, Tumor ; Cell Proliferation/physiology ; Cohort Studies ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Drug Resistance, Neoplasm ; ELAV-Like Protein 1/genetics ; Humans ; Isocitrate Dehydrogenase/genetics ; Mice ; Mice, Nude ; Organoplatinum Compounds/pharmacology ; Oxaliplatin ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Phenotype ; Protein Processing, Post-Translational ; Survival Analysis ; Transcriptional Activation ; Transfection ; Up-Regulation ; Gemcitabine |
| مستخلص: | 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. Cancer Res; 77(16); 4460-71. ©2017 AACR . (©2017 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | R01 CA188652 United States CA NCI NIH HHS; R01 CA212600 United States CA NCI NIH HHS; T32 EB009380 United States EB NIBIB NIH HHS |
| المشرفين على المادة: | 0 (ELAV-Like Protein 1) 0 (Organoplatinum Compounds) 04ZR38536J (Oxaliplatin) 0W860991D6 (Deoxycytidine) EC 1.1.1.41 (Isocitrate Dehydrogenase) EC 1.1.1.42. (IDH1 protein, human) 0 (Gemcitabine) |
| تواريخ الأحداث: | Date Created: 20170628 Date Completed: 20170929 Latest Revision: 20221207 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC5922269 |
| DOI: | 10.1158/0008-5472.CAN-17-0015 |
| PMID: | 28652247 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-17-0015 |