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

doi:10.1016/j.isci.2022.104442

Iloprost requires the Frizzled-9 receptor to prevent lung cancer

iScience. 2022 May 23;25(6):104442. doi: 10.1016/j.isci.2022.104442. eCollection 2022 Jun 17.

Authors

Affiliations

¹ Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³ National Jewish Health, Denver, CO, USA.
⁴ Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.

Abstract

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 Fzd ₉ ^-/- mouse would not be protected by iloprost in a lung cancer model. Fzd ₉ ^-/- mice were treated with inhaled iloprost in a urethane model of lung adenoma. We found that Fzd ₉ ^-/- 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.

Keywords: Biochemistry; Biological sciences; Cancer.

Abstract

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