title: Upregulation of cugbp2 increases response of pancreatic cancer cells to chemotherapy.
abstract: OBJECTIVE
  Altered expression and/or function of ribosomal RNA (rRNA)-binding proteins CUGBP2/CELF2 might influence post-transcriptional regulation of the HO-1- and COX-2-mediated cytoprotective pathways and represents an important therapeutic target. The aim of this study was to assess the effects of CUGBP2-mediated post-transcriptional regulation of COX-2 and HO-1 in pancreatic cancer cells in regard of response to gemcitabine (GEM) treatment.
  
  
  METHODS
  Expression of CUGBP2, COX-2, and HO-1 was evaluated using qRT-PCR and Western blot methods. Cell viability after treatment with GEM and/or curcumin and siCUGBP2 was evaluated using MTT and crystal violet tests. RNA immunoprecipitation analysis was used to confirm COX-2 and HO-1 post-transcriptional regulation by CUGBP2 protein.
  
  
  RESULTS
  CUGBP2 expression at the messenger RNA (mRNA) level was 2.2-fold lower (p = 0.007), but HO-1 and COX-2 expression was increased 6.9- (p = 0.023) and 2.3- (p = 0.046) fold in pancreatic cancer tissues. The median survival of patients with low CUGBP2 expression from the lowest tercile was 13.8 months. The median survival of patients in terciles of middle and high CUGBP2 expression levels was 21.9 month (p = 0.123). Induction of CUGBP2 expression by curcumin resulted in the downregulation of HO-1 and COX-2 and strongly sensitized tumor cells to GEM treatment. However, CUGBP2 silencing upregulated HO-1 and COX-2 protein expression and had a high effect on cells viability.
  
  
  CONCLUSIONS
  Decreased activity of CUGBP2 could be associated with high chemoresistance and early dissemination of pancreatic cancer through the HO-1- and COX-2-mediated cytoprotective and carcinogenesis pathways. Curcumin significantly increased the effectiveness of GEM treatment in vitro via the CUGBP2-mediated post-transcriptional regulation pathway.
authors.affiliation: Institute for Digestive System Research, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, 50161, Lithuania. aldona.jakstaite@gmail.com.
authors.forename: Aldona
authors.initials: A
authors.lastname: Jakstaite
authors.affiliation: Institute for Digestive System Research, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, 50161, Lithuania.
authors.forename: Aurelija
authors.initials: A
authors.lastname: Maziukiene
authors.affiliation: Institute for Digestive System Research, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, 50161, Lithuania.
authors.forename: Giedre
authors.initials: G
authors.lastname: Silkuniene
authors.affiliation: Institute for Digestive System Research, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, 50161, Lithuania.
authors.forename: Kristina
authors.initials: K
authors.lastname: Kmieliute
authors.affiliation: Institute for Digestive System Research, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, 50161, Lithuania.|Department of Surgery, Lithuanian University of Health Sciences, Eiveniu str. 2, Kaunas, 50161, Lithuania.
authors.forename: Albertas
authors.initials: A
authors.lastname: Dauksa
authors.affiliation: Department of Surgery, Lithuanian University of Health Sciences, Eiveniu str. 2, Kaunas, 50161, Lithuania.|Department of Obstetrics and Gynaecology, Lithuanian University of Health Sciences, Eiveniu str. 2, Kaunas, 50161, Lithuania.
authors.forename: Saulius
authors.initials: S
authors.lastname: Paskauskas
authors.affiliation: Institute for Digestive System Research, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, 50161, Lithuania.|Department of Surgery, Lithuanian University of Health Sciences, Eiveniu str. 2, Kaunas, 50161, Lithuania.
authors.forename: Antanas
authors.initials: A
authors.lastname: Gulbinas
authors.affiliation: Institute for Digestive System Research, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, 50161, Lithuania.|Department of Surgery, Lithuanian University of Health Sciences, Eiveniu str. 2, Kaunas, 50161, Lithuania.
authors.forename: Zilvinas
authors.initials: Z
authors.lastname: Dambrauskas
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000067878:CELF Proteins / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000067878:CELF Proteins; C117363:CELF2 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2
keywords: COX-2 (PTGS2); CUGBP2 (CELF2); HO-1 (HMOX1); Pancreatic cancer; Post-transcriptional regulation