title: Knockdown or inhibition of aldo-keto reductase 1B10 inhibits pancreatic carcinoma growth via modulating Kras-E-cadherin pathway.
abstract: Aldo-keto reductase 1B10 (AKR1B10) has relatively specific lipid substrates including carbonyls, retinal and farnesal/geranylgeranial. Metabolizing these lipid substrates appears crucial to carcinogenesis, particularly for farnesal/geranylgeranial that involves protein prenylation. Mutant Kras is a most common active oncogene in pancreatic cancer, and its activation requires protein prenylation. To directly determine the role of AKR1B10 in pancreatic carcinogenesis, we knocked down AKR1B10 in CD18 human pancreatic carcinoma cells using shRNA approach. Silencing AKR1B10 resulted in a significant inhibition of anchor-dependent growth (knockdown cells vs. vector-control cells: 67 ± 9.5 colonies/HPF vs. 170 ± 3.7 colonies/HPF, p < 0.01), invasion index (0.27 vs. 1.00, p < 0.05), and cell migration (at 16 hours 9.2 ± 1.2% vs. 14.0 ± 1.8%, at 24 hours 21.0 ± 1.1% vs. 30.5 ± 3.5%, and at 48 hours 51.9 ± 5.7% vs. 88.9 ± 3.0%, p < 0.01). Inhibition of AKR1B10 by oleanolic acid (OA) showed a dose-dependent inhibition of cell growth with IC50 at 30 µM. Kras pull-down and Western blot analysis revealed a significant down-regulation of active form Kras and phosphorylated C-Raf, and Erk, as well as an up-regulation of E-cadherin. A significant reduction of in vivo tumor growth was observed in nude mice implanted with the CD18 pancreatic carcinoma cells with AKR1B10 knockdown (tumor weight: 0.25 ± 0.06 g vs. 0.52 ± 0.07 g, p = 0.01), and with OA treatment (tumor weight: 0.35 ± 0.05 g vs. 0.52 ± 0.07 g, p = 0.05). Our findings indicate AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis via modulation of the Kras-E-cadherin pathway.
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Wanying
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Haonan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Yihe
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: g-yang@northwestern.edu.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000074408:Aldo-Keto Reductases; D000818:Animals; D018821:CD18 Antigens / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009828:Oleanolic Acid / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018821:CD18 Antigens; D015820:Cadherins; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D009828:Oleanolic Acid; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: AKR1B10; E-cadherin; Invasion; KRAS; Migration; Pancreatic adenocarcinoma