title: MicroRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by regulating PPP2R1B expression in colorectal cancer.
abstract: Drug resistance is one of the major hurdles for cancer treatment. However, the underlying mechanisms are still largely unknown and therapeutic options remain limited. In this study, we show that microRNA (miR)-587 confers resistance to 5-fluorouracil (5-FU)-induced apoptosis in vitro and reduces the potency of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-587 modulates drug resistance through downregulation of expression of PPP2R1B, a regulatory subunit of the PP2A complex, which negatively regulates AKT activation. Knockdown of PPP2R1B expression increases AKT phosphorylation, which leads to elevated XIAP expression and enhanced 5-FU resistance; whereas rescue of PPP2R1B expression in miR-587-expressing cells decreases AKT phosphorylation/XIAP expression, re-sensitizing colon cancer cells to 5-FU-induced apoptosis. Moreover, a specific and potent AKT inhibitor, MK2206, reverses miR-587-conferred 5-FU resistance. Importantly, studies of colorectal cancer specimens indicate that the expression of miR-587 and PPP2R1B positively and inversely correlates with chemoresistance, respectively, in colorectal cancer. These findings indicate that the miR-587/PPP2R1B/pAKT/XIAP signaling axis has an important role in mediating response to chemotherapy in colorectal cancer. A major implication of our study is that inhibition of miR-587 or restoration of PPP2R1B expression may have significant therapeutic potential to overcome drug resistance in colorectal cancer patients and that the combined use of an AKT inhibitor with 5-FU may increase efficacy in colorectal cancer treatment.
authors.affiliation: 1] Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, Omaha, NE 68198, USA [2] Department of Genetics, Cell Biology and Anatomy, 985950 Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: G
authors.initials: G
authors.lastname: Talmon
authors.affiliation: 1] Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, Omaha, NE 68198, USA [2] Department of Genetics, Cell Biology and Anatomy, 985950 Nebraska Medical Center, Omaha, NE 68198, USA [3] Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, 985950 Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D006575:Heterocyclic Compounds, 3-Ring; C000606494:MIRN587 microRNA, human; C548887:MK 2206; D035683:MicroRNAs; C432785:PPP2R1B protein, human; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D005472:Fluorouracil