title: Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues.
abstract: OBJECTIVE
  To prevent chemotherapy-related side effects, synthetic glucocorticoids, for example, dexamethasone, are routinely administered to patients with ovarian cancer. However, preclinical data implicate glucocorticoids in suppressing chemotherapy-mediated apoptosis in epithelial tumors. The anti-apoptotic mechanisms underlying this increased survival have been shown to require up-regulation of prosurvival genes, including serum and glucocorticoid-regulated kinase 1 (SGK1) and map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Despite abundant preclinical data, there are no correlative studies in patients. We therefore evaluated anti-apoptotic gene expression in tumor samples from patients randomized to dexamethasone or normal saline.
  
  
  METHODS
  Eighteen patients were randomized before exploratory laparotomy for suspected ovarian cancer. Dexamethasone or normal saline was administered i.v. following anesthesia. Ovarian and omental tumor samples were collected intra-operatively before and after infusion. Samples were analyzed for histology and glucocorticoid receptor expression by immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were determined using quantitative real-time PCR.
  
  
  RESULTS
  Ten patients were evaluable. At 30 min postinfusion, tumor samples from five patients receiving dexamethasone revealed an average SGK1 mRNA induction of 6.1-fold (SEM, +/-2.6) compared with only 1.5-fold (SEM, +/-0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, +/-2.9) following dexamethasone versus 1.1-fold (SEM, +/-0.4) following normal saline (P = 0.009). All samples expressed glucocorticoid receptor.
  
  
  CONCLUSIONS
  Glucocorticoid administration to patients is associated with rapid up-regulation of SGK1 and MKP1 expression in ovarian tumors. This finding supports the hypothesis that pharmacologic doses of glucocorticoids may decrease chemotherapy effectiveness in ovarian cancer patients through increased anti-apoptotic gene expression.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Melhem
authors.forename: S Diane
authors.initials: SD
authors.lastname: Yamada
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: Bertha
authors.initials: B
authors.lastname: Delgado
authors.forename: Deanna R
authors.initials: DR
authors.lastname: Brickley
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Conzen
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D003907:Dexamethasone / Q000008:administration & dosage* / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010919:Placebos; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D010919:Placebos; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000099184:Serum-Glucocorticoid Regulated Kinases; C517019:DUSP1 protein, human