title: Role of LKB1-CRTC1 on glycosylated COX-2 and response to COX-2 inhibition in lung cancer.
abstract: BACKGROUND
  Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins including PGE-2 linking inflammation with mitogenic signaling. COX-2 is also an anticancer target, however, treatment strategies have been limited by unreliable expression assays and by inconsistent tumor responses to COX-2 inhibition.
  
  
  METHODS
  We analyzed the TCGA and Director's Challenge lung cancer datasets (n = 188) and also generated an LKB1-null lung cancer gene signature (n = 53) to search the Broad Institute/Connectivity-MAP (C-MAP) dataset. We performed ChIP analyses, real-time polymerase chain reaction, immunoblotting, and drug testing of tumor cell lines (n = 8) and primary lung adenocarcinoma surgical resections (n = 13).
  
  
  RESULTS
  We show that COX-2 is a target of the cAMP/CREB coactivator CRTC1 signaling pathway. In addition, we detected a correlation between LKB1 status, CRTC1 activation, and presence of glycosylated, but not inactive hypoglycosylated COX-2 in primary lung adenocarcinoma. A search of the C-MAP drug database discovered that all high-ranking drugs positively associated with the LKB1-null signature are known CRTC1 activators, including forskolin and six different PGE-2 analogues. Somatic LKB1 mutations are present in 20.0% of lung adenocarcinomas, and we observed growth inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1 as compared with LKB1-wildtype cells (NS-398, P = .002 and Niflumic acid, P = .006; two-tailed t test).
  
  
  CONCLUSIONS
  CRTC1 activation is a key event that drives the LKB1-null mRNA signature in lung cancer. We also identified a positive feedback LKB1/CRTC1 signaling loop for COX-2/PGE2 regulation. These data suggest a role for LKB1 status and glycosylated COX-2 as specific biomarkers that provide a framework for selecting patients for COX-2 inhibition studies.
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Chunxia
authors.initials: C
authors.lastname: Cao
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Ruli
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Amelio
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Zirong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Yumei
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Chengbin
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Eric A
authors.initials: EA
authors.lastname: Welsh
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Brienne E
authors.initials: BE
authors.lastname: Engel
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
authors.forename: Maria
authors.initials: M
authors.lastname: Zajac-Kaye
authors.affiliation: Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK). fkaye@ufl.edu.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Kaye
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D018579:Patient Selection; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C500984:CRTC1 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D014157:Transcription Factors; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D015232:Dinoprostone