Iloprost requires the Frizzled-9 receptor to prevent lung cancer
Kayla Sompel,
Lori D. Dwyer-Nield,
Alex J. Smith,
Alamelu Elango,
Don S. Backos,
Bicheng Zhang,
James Gross,
Kristina Ternyak,
Jennifer L. Matsuda,
Katrina Kopf,
Robert L. Keith,
Meredith A. Tennis
Affiliations
Kayla Sompel
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Lori D. Dwyer-Nield
Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Alex J. Smith
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Alamelu Elango
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Don S. Backos
Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Bicheng Zhang
National Jewish Health, Denver, CO, USA
James Gross
National Jewish Health, Denver, CO, USA
Kristina Ternyak
National Jewish Health, Denver, CO, USA
Jennifer L. Matsuda
National Jewish Health, Denver, CO, USA
Katrina Kopf
National Jewish Health, Denver, CO, USA
Robert L. Keith
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Rocky Mountain Regional VA Medical Center, Aurora, CO, USA
Meredith A. Tennis
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Corresponding author
Summary: Prevention of premalignant lesion progression is a promising approach to reducing lung cancer burden in high-risk populations. Substantial preclinical and clinical evidence has demonstrated efficacy of the prostacyclin analogue iloprost for lung cancer chemoprevention. Iloprost activates peroxisome proliferator-activated receptor gamma (PPARG) to initiate chemopreventive signaling and in vitro, which requires the transmembrane receptor Frizzled9 (FZD9). We hypothesized a Fzd9−/− mouse would not be protected by iloprost in a lung cancer model. Fzd9−/− mice were treated with inhaled iloprost in a urethane model of lung adenoma. We found that Fzd9−/− mice treated with iloprost were not protected from adenoma development compared to wild-type mice nor did they demonstrate increased activation of iloprost signaling pathways. Our results established that iloprost requires FZD9 in vivo for lung cancer chemoprevention. This work represents a critical advancement in defining iloprost’s chemopreventive mechanisms and identifies a potential response marker for future clinical trials.
