title: Glucocorticoid receptor status is a principal determinant of variability in the sensitivity of non-small-cell lung cancer cells to pemetrexed.
abstract: BACKGROUND
  Pemetrexed is an S-phase targeted drug in front-line or maintenance therapy of advanced nonsquamous non-small-cell lung cancer (NSCLC) but methods are needed for predicting the drug response. Dexamethasone is typically administered the day before, the day of, and the day after pemetrexed. As dexamethasone strongly regulates many genes including p53 through the glucocorticoid receptor (GR), we hypothesized that dexamethasone influences tumor response to pemetrexed.
  
  
  METHODS
  Eight nonsquamous NSCLC cell line models with varied p53 and GRα/GRβ status were used for gene expression and cell-cycle analyses and for loss- or gain-of-function experiments.
  
  
  RESULTS
  In three cell lines dexamethasone profoundly, but reversibly, suppressed the fraction of S-phase cells. Dexamethasone also reversibly repressed expression of thymidylate synthase and dihydrofolate reductase, which are primary targets of pemetrexed but are also quintessential S-phase enzymes as well as the S-phase-dependent expression of thymidine kinase 1. Dexamethasone also decreased expression of the major pemetrexed transporters, the reduced folate carrier and the proton coupled folate transporter. Only cells expressing relatively high GRα showed these dexamethasone effects, regardless of p53 status. In cells expressing low GRα, the dexamethasone response was rescued by ectopic GRα. Further, depletion of p53 did not attenuate the dexamethasone effects. The presence of dexamethasone during pemetrexed treatment protected against pemetrexed cytotoxicity in only the dexamethasone responsive cells.
  
  
  CONCLUSIONS
  The results predict that in nonsquamous NSCLC tumors, reversible S-phase suppression by dexamethasone, possibly combined with a reduction in the drug transporters, attenuates responsiveness to pemetrexed and that GR status is a principal determinant of tumor variability of this response.
authors.affiliation: Barbara Ann Karmanos Cancer Institute, and Department of Oncology, Wayne State University, Detroit, Michigan.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Patki
authors.forename: Shirish
authors.initials: S
authors.lastname: Gadgeel
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Huang
authors.forename: Thomas
authors.initials: T
authors.lastname: McFall
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Shields
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Manohar
authors.initials: M
authors.lastname: Ratnam
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage; D004357:Drug Synergism; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068437:Pemetrexed; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D005971:Glutamates; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D000068437:Pemetrexed; D006147:Guanine; D003907:Dexamethasone
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