title: micorRNA-101 silences DNA-PKcs and sensitizes pancreatic cancer cells to gemcitabine.
abstract: Gemcitabine sensitization is important for the treatment of pancreatic cancer. We have previously shown that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) over-expression causes Akt activation and gemcitabine resistance in pancreatic cancer cells. Here, we aim to downregulate DNA-PKcs via introduction of micorRNA-101 ("miR-101"). We showed that forced-expression of miR-101 downregulated DNA-PKcs and potentiated gemcitabine-induced PANC-1 pancreatic cancer cell death and apoptosis. Contrarily, miR-101 depletion through expressing antagomiR-101 in PANC-1 cells resulted in DNA-PKcs upregulation and gemcitabine resistance. DNA-PKcs downregulation is the primary reason of gemcitabine-sensitization by miR-101. DNA-PKcs inhibition (by NU7026) or silence (by targeted siRNAs) disabled miR-101-mediaetd gemcitabine sensitization. Significantly, Akt Ser-473 phosphorylation in PANC-1 cells was also inhibited by miR-101, but was augmented with antagomiR-101 expression. Importantly, we showed that miR-101 level was downregulated in gemcitabine-resistant human pancreatic cancer tissues, which was correlated with DNA-PKcs upregulation. Together, these results suggest that miR-101 sensitizes PANC-1 cells to gemcitabine possibly via downregulating DNA-PKcs.
authors.affiliation: Department of Hepatopancreatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province, China. Electronic address: haohu@ntu.edu.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of General Surgery, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of General Surgery, The Second People's Hospital of Wuhu, Wuhu, China.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatopancreatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province, China.
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Hepatopancreatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province, China.
authors.forename: Benshun
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Hepatopancreatobiliary Center, The Third Hospital Affiliated to Nantong University, Wuxi City, Jiangsu Province, China. Electronic address: guyuanlongnty@163.com.
authors.forename: YuanLong
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000070416:Antagomirs / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics; D010766:Phosphorylation; D000093542:Gemcitabine
chemical_list: C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D000070416:Antagomirs; D000964:Antimetabolites, Antineoplastic; D002867:Chromones; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D009025:Morpholines; D009687:Nuclear Proteins; D003841:Deoxycytidine; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D000093542:Gemcitabine
keywords: DNA-PKcs; Gemcitabine; Pancreatic cancer and Akt; micorRNA-101