Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas

Xiong, Donghai; Pan, Jing; Zhang, Qi; Szabó, Éva; Miller, Mark Steven; Lubet, Ronald A.; Wang, Yian; You, Ming

doi:10.1172/jci.insight.94220

Cited by 2 publications

(2 citation statements)

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“…Pioglitazone exhibits anticancer effects in lung cancer cells, including reducing proliferation, altering ROS levels, downregulating MAPK signaling, reversing elevated glucose metabolism, altering miRNA expression, decreasing prostaglandin E2 (PGE2), increasing 15‐hydroxyprostaglandin dehydrogenase (15‐Hpgd) and reversing epithelial to mesenchymal transition (EMT) 13‐17 . In murine studies, pioglitazone abrogates increased MYC signaling, reduces glucose metabolism, increases PPARγ anticancer transcriptional activity and inhibits angiogenesis 10,18‐20 …”

Section: Introductionmentioning

confidence: 99%

“…[13][14][15][16][17] In murine studies, pioglitazone abrogates increased MYC signaling, reduces glucose metabolism, increases PPARγ anticancer transcriptional activity and inhibits angiogenesis. 10,[18][19][20] Our group has shown that high grade, persistent dysplasias have the greatest risk of progressing to invasive squamous cell carcinoma, and pioglitazone may be one agent that can target the most dangerous lesions and improve endobronchial dysplasia. 21 The NTCU model generates premalignant lesions similar to those linked with increased risk of squamous lung cancer and offers a context in which to explore mechanisms and markers of pioglitazone chemoprevention.…”

Section: Introductionmentioning

confidence: 99%

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PPARgamma agonism inhibits progression of premalignant lesions in a murine lung squamous cell carcinoma model

Dwyer‐Nield

McArthur²,

Hudish³

et al. 2022

Intl Journal of Cancer

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The N‐nitroso‐trischloroethylurea (NTCU)‐induced mouse model of squamous lung carcinoma recapitulates human disease from premalignant dysplasia through invasive tumors, making it suitable for preclinical chemoprevention drug testing. Pioglitazone is a peroxisome proliferator‐activated receptor γ (PPARγ) agonist shown to prevent lung tumors in preclinical models. We investigated pioglitazone's effect on lesion development and markers of potential preventive mechanisms in the NTCU model. Female FVB/N mice were exposed to vehicle, NTCU or NTCU + oral pioglitazone for 32 weeks. NTCU induces the appearance of basal cells in murine airways while decreasing/changing their epithelial cell makeup, resulting in development of bronchial dysplasia. H&E and keratin 5 (KRT5) staining were used to detect and grade squamous lesions in formalin fixed lungs. mRNA expression of epithelial to mesenchymal transition (EMT) markers and basal cell markers were measured by qPCR. Dysplasia persistence markers desmoglein 3 and polo like kinase 1 were measured by immunohistochemistry. Basal cell markers KRT14 and p63, club cell specific protein and ciliated cell marker acetylated tubulin were measured by immunofluorescence. Pioglitazone treatment significantly reduced squamous lesions and the presence of airway basal cells, along with increasing normal epithelial cells in the airways of NTCU‐exposed mice. Pioglitazone also significantly influenced EMT gene expression to promote a more epithelial, and less mesenchymal, phenotype. Pioglitazone reduced the presence of squamous dysplasia and maintained normal airway cell composition. This work increases the knowledge of mechanistic pathways in PPARγ agonism for lung cancer interception and provides a basis for further investigation to advance this chemoprevention strategy.

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Section: Introductionmentioning

confidence: 99%