Role of LKB1-CRTC1 on glycosylated COX-2 and response to COX-2 inhibition in lung cancer

J Natl Cancer Inst. 2014 Dec 1;107(1):358. doi: 10.1093/jnci/dju358. Print 2015 Jan.

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).

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenocarcinoma / surgery
  • Adenocarcinoma of Lung
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / therapeutic use*
  • Dinoprostone / metabolism
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / surgery
  • Fluorescent Antibody Technique
  • Glycosylation
  • Humans
  • Immunoblotting
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / surgery
  • Patient Selection
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • Transcription Factors / metabolism*

Substances

  • Antineoplastic Agents
  • CRTC1 protein, human
  • Cyclooxygenase 2 Inhibitors
  • Transcription Factors
  • Cyclic AMP
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases
  • Dinoprostone